Acetindine derivatives, their preparation and medicaments containing them

ABSTRACT

Disclosed are azetidine derivatives of formula:  
                 
 
     their optical isomers, their salts, their preparation and medicaments containing them.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.09/803,723, filed Mar. 9, 2001, which is a continuation of InternationalApplication No. PCT/FR99/02147, filed Sep. 9, 1999, and claims thebenefit of U.S. Provisional Application No, 60/119,929, filed on Feb.12, 1999, and of French Patent Application FR98/11342, filed on Sep. 11,1998.

SUMMARY OF THE INVENTION

[0002] The present invention relates to azetidine derivatives offormula:

[0003] their optical isomers, their salts, their preparation andmedicaments containing them, as well as to methods of using thesederivatives to treat a variety of medical conditions and disorders.

DETAILED DESCRIPTION

[0004] In formula (I),

[0005] R represents a chain

[0006] R₁ represents a methyl or ethyl radical,

[0007] R₂ represents either an aromatic chosen from phenyl, naphthyl orindenyl, these aromatics being nonsubstituted or substituted with one ormore halogens, alkyl, alkoxy, —CO-alk, hydroxyl, —COOR₅, formyl,trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,—NR₆R₇, —CO—NH—NR₆R₇, —N(alk)COOR , cyano, —CONHR₉, —CO—NR₁₆R₁₇,alkylsulfanyl, hydroxyalkyl, —O-alk-NR₁₂R₁₃ or alkylthioalkyl or aheteroaromatic chosen from the benzofuryl, benzothiazolyl, benzothienyl,benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl,indolinyl, isochromanyl, isoquinolyl, pyridyl, quinolyl,1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl, orthienyl rings, it being possible for these heteroaromatics to benonsubstituted or substituted with a halogen, alkyl, alkoxy, —COOR₅,trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy, nitro,—NR₆R₇, —CO—NH—NR₆R₇, cyano, —CONHR₉, alkylsulfanyl, hydroxyalkyl oralkylthioalkyl,

[0008] R₃ and R₄, which are identical or different, represent either anaromatic chosen from phenyl, naphthyl or indenyl, these aromatics beingnonsubstituted or substituted with one or more halogens, alkyl, alkoxy,formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, —CO-alk, cyano,—COOR₅, —CONR₁₀R₁₁, —CO—NH—NR₆R₇, alkylsulfanyl, hydroxyalkyl,-alk-NR₆R₇ or alkylthioalkyl; or a heteroaromatic chosen frombenzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromanyl,isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,thiazolyl or thienyl rings, it being possible for these heteroaromaticsto be nonsubstituted or substituted with a halogen, alkyl, alkoxy,hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, —COOR₅,—CO—NH—NR₆R₇, —CONR₁₀R₁₁, -alk-NR₆R₇, alkylsulfanyl, hydroxyalkyl oralkylthioalkyl;

[0009] R₅ is an alkyl or phenyl radical which is optionally substitutedwith one or more halogen atoms,

[0010] R₆ and R₇, which are identical or different, represent a hydrogenatom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk orhydroxyalkyl radical or alternatively R₆ and R₇ together form with thenitrogen atom to which they are attached a 3- to 10-membered saturatedor unsaturated mono- or bicyclic heterocycle optionally containinganother heteroatom chosen from oxygen, sulfur and nitrogen and beingoptionally substituted with one or more alkyl, —COalk, —COOalk,—CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo, hydroxyalkyl, -alk-O-alk or—CO—NH₂ radicals,

[0011] R₈ represents an alkyl radical,

[0012] R₉ represents a hydrogen atom or an alkyl radical or an alkylradical substituted with a dialkylamino, phenyl, cycloalkyl (optionallysubstituted with —COOalk) or a 3- to 10-membered saturated orunsaturated mono- or bicyclic heterocycle optionally containing one ormore heteroatoms chosen from oxygen, sulfur and nitrogen and beingoptionally substituted with one or more alkyl radicals,

[0013] R₁₀ and R₁₁, which are identical or different, represent ahydrogen atom or an alkyl radical or alternatively R₁₀ and R₁ togetherform with the nitrogen atom to which they are attached a 3- to10-membered saturated mono- or bicyclic heterocycle optionallycontaining another heteroatom chosen from oxygen, sulfur and nitrogenand being optionally substituted with an alkyl radical, R₁₂ and R₁₃,which are identical or different, represent a hydrogen atom or an alkylor cycloalkyl radical or alternatively R₁₂ and R₁₃ together form withthe nitrogen atom to which they are attached a 3- to 10-memberedsaturated mono- or bicyclic heterocycle optionally containing anotherheteroatom chosen from oxygen, sulfur and nitrogen and being optionallysubstituted with an alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk or—CO-alk-NR₁₄R₁₅ radical or a 3- to 10-membered saturated mono- orbicyclic heterocycle containing a heteroatom chosen from oxygen, sulfurand nitrogen,

[0014] R₁₄ and R₁₅, which are identical or different, represent ahydrogen atom or an alkyl or —COOalk radical,

[0015] R₁₆ and R₁₇ together form with the nitrogen atom to which theyare attached a 3- to 10-membered saturated mono- or bicyclic heterocycleoptionally containing another heteroatom chosen from oxygen, sulfur andnitrogen,

[0016] R′ represents a hydrogen atom or a —CO-alk radical, alkrepresents an alkyl or alkylene radical.

[0017] In the preceding definitions and in those which follow, unlessotherwise stated, the alkyl and alkylene radicals and portions and thealkoxy radicals and portions are in the form of a straight or branchedchain and contain 1 to 6 carbon atoms.

[0018] Among the alkyl radicals, there may be mentioned methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyland hexyl radicals. Among the alkoxy radicals, there may be mentionedmethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy and pentyloxy radicals.

[0019] The term halogen comprises chlorine, fluorine, bromine andiodine.

[0020] When R₂ and/or R₃ and/or R₄ represent independently a substitutedphenyl, the latter is preferably mono-, di- or trisubstituted.

[0021] When R₆ and R₇ together form with the nitrogen atom to which theyare attached a 3- to 10-membered saturated or unsaturated mono- orbicyclic heterocycle, the latter is preferably an azetidinyl,pyrrolidinyl, piperazinyl, piperidyl, morpholinyl, imidazolyl,thiomorpholinyl or furyl ring, these rings being optionally substitutedwith an alkyl, hydroxyalkyl, -alk-O-alk, —CONH₂, —COalk, —COOalk, oxo,—CSNHalk, —CONHalk or —CO-alk-NR₁₄R₁₅ radical and, in particular, with amethyl, ethyl, propyl, isobutyl, acetyl,N,N-dimethylaminomethylcarbonyl, methyloxycarbonyl, methylcarbamoyl,methylthiocarbamoyl, N-methylaminomethylcarbonyl,N-methyl-N-tertbutoxycarbonylaminomethylcarbonyl, oxo, —CSNHCH₃ or—CONHCH₃ radical.

[0022] When R₁₀ and R₁₁ together form with the nitrogen atom to whichthey are attached a 3- to 10-membered saturated mono- or bicyclicheterocycle, the latter is preferably an azetidinyl, pyrrolidinyl,piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these ringsbeing optionally substituted with an alkyl.

[0023] When R₁₂ and R₁₃ form together with the nitrogen atom to whichthey are attached a 3- to 10-membered saturated mono- or bicyclicheterocycle, the latter is preferably an azetidinyl, pyrrolidinyl,piperazinyl, piperidyl, morpholinyl or thiomorpholinyl ring, these ringsbeing optionally substituted with an alkyl, —COalk, —COOalk, —CO—NHalk,—CS—NHalk or —CO-alk-NR₁₄R₁₅ radical or a 3- to 10-membered saturatedmono- or bicyclic heterocycle containing a heteroatom chosen fromoxygen, sulfur and nitrogen, and, in particular, with a thiomorpholinylradical.

[0024] When R₁₆ and R₁₇ together form with the nitrogen atom to whichthey are attached a 3- to 10-membered saturated mono- or bicyclicheterocycle, the latter is preferably a piperidyl ring.

[0025] When R₉ represents an alkyl radical substituted with a 3- to10-membered saturated or unsaturated mono- or bicyclic heterocycleoptionally containing one or more heteroatoms chosen from oxygen, sulfurand nitrogen, the latter is preferably a pyrrolidinyl, tetrahydrofuryl,morpholinyl or pyrrolyl ring, these rings being optionally substitutedwith one or more alkyl radicals.

[0026] The compounds of formula (I) may be provided in the form ofenantiomers and diastereoisomers. These optical isomers and mixturesthereof form part of the invention.

[0027] The compounds of formula (I) for which R represents a chain offormula (A) may be prepared by dehydration of a corresponding compoundof formula (Ia)

[0028] in which R₁, R₂, R₃ and R₄ have the same meanings as in formula(I) and R″ represents a hydroxyl, methanesulfonyloxy or acetyloxyradical.

[0029] This dehydration is carried out by any method known to personsskilled in the art which makes it possible to dehydrate an alcohol orone of its derivatives in order to obtain the corresponding alkene.Preferably, derivatives are used for which R″ is a methanesulfonyloxy oracetyloxy radical obtained from the corresponding derivative for whichR″ is a hydroxyl radical by the action of methanesulfonyl chloride oracetyl chloride, in an inert solvent such as pyridine, tetrahydrofuran,dioxane, a chlorinated solvent (dichloromethane or chloroform forexample), at a temperature of between 5° C. and 20° C. and then themedium is treated with a base such as an alkali metal hydroxide (sodiumhydroxide for example), an alkali metal carbonate (sodium or potassiumcarbonate for example), an amine such as a trialkylamine (triethylaminefor example), 4-dimethylaminopyridine,diaza-1,8-bicyclo[5.4.0]undec-7-ene, at a temperature of between 0° C.and the boiling temperature of the reaction mixture. Themethanesulfonyloxy and the acetyloxy may be isolated or otherwise.

[0030] The compounds of formula (I) for which R represents a chain (B)in which R′ is a hydrogen atom may be prepared by reacting thederivative R₁SO₂CH₂R₂ (II) for which R₁ and R₂ have the same meanings asin formula (I) with an azetidinone of formula:

[0031] in which R₃ and R₄ have the same meanings as in formula (I).

[0032] The procedure is generally carried out in an inert solvent suchas an ether (tetrahydrofuran for example), in the presence of a strongbase such as lithium diisopropylamide, potassium tert-butoxide orn-butyllithium, at a temperature of between −70° C. and −15° C.

[0033] The derivatives of formula (II) may be obtained by application oradaptation of the methods described in the examples. In particular, theprocedure is carried out according to the following reaction schemes:

[0034] In these formulae Hal represents a halogen atom and, preferably,chlorine, bromine or iodine, R₁ and R₂ have the same meanings as informula (I).

[0035] The reaction (a) is generally carried out in an inert solventsuch as dimethylformamide or a 1-4C. aliphatic alcohol, at a temperatureof between 20 and 30° C.

[0036] The reaction (b) is carried out by any known method which makesit possible to oxidize a sulfur-containing derivative without affectingthe rest of the molecule such as the methods described by M. HUDLICKY,Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). Forexample, the procedure is carried out by the action of an organic peroxyacid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonicacids, especially peroxybenzoic acid, 3-chloroperoxybenzoic acid,4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyaceticacid, peroxyformic acid or monoperoxyphthalic acid) or in organicperacids or a salt of such an acid (for example periodic or persulfuricacid), in an inert solvent such as a chlorinated solvent (chloroform ordichloromethane for example), at a temperature of between 0 and 25° C.It is also possible to use hydrogen peroxide or a periodate (sodiumperiodate for example), in an inert solvent such as 1-4C aliphaticalcohol (methanol or ethanol for example), water or a mixture of thesesolvents, at a temperature of between 0 and 20° C. It is also possibleto carry out the procedure using tertbutyl hydroperoxide in the presenceof titanium tetraisopropoxide in a 1-4C aliphatic alcohol (methanol orethanol for example) or a water-alcohol mixture, at a temperature closeto 25° C. or using oxone^(R) (potassium peroxymonosulfate), in a 1-4Caliphatic alcohol (methanol or ethanol for example), in the presence ofwater, acetic acid or sulfuric acid, at a temperature close to 20° C.

[0037] The reaction (c) is preferably carried out in an inert solventsuch as a 1-4C aliphatic alcohol (methanol or ethanol for example), at atemperature of between 20° C. and the boiling temperature of thereaction medium.

[0038] The derivatives of formula (IV) are commercially available or maybe obtained by application or adaptation of the methods described in theexamples. In particular, the methylated derivative or the correspondingalcohol is halogenated using a halogenating agent such as hydrobromicacid, in acetic acid, at a temperature close to 20° C. or N-bromo- orchlorosuccinimide in the presence of benzoyl peroxide, in an inertsolvent such as tetrachloromethane, at the boiling temperature of thereaction medium. The methylated derivatives or the correspondingalcohols are commercially available or may be obtained according to themethods described by BRINE G. A. et al., J. Heterocycl. Chem., 26, 677(1989) and NAGARATHNAM D., Synthesis, 8, 743 (1992) and in the examples.

[0039] The azetidinones of formula (III) may be obtained by applicationor adaptation of the methods described by KATRITZKY A. R. et al., J.Heterocycl. Chem., 271 (1994) or DAVE P. R., J. Org. Chem., 61, 5453(1996) and in the examples. The procedure is generally carried outaccording to the following reaction scheme:

[0040] In these formulae, R₃ and R₄ have the same meanings as in formula(I) and X represents a chlorine or bromine atom.

[0041] In step A, the procedure is preferably carried out in an inertsolvent such as a 1-4C aliphatic alcohol (ethanol or methanol forexample), optionally in the presence of an alkali metal hydroxide, atthe boiling temperature of the reaction medium.

[0042] In step B, the reduction is generally carried out using lithiumaluminum hydride, in tetrahydrofuran at the boiling temperature of thereaction medium.

[0043] In step C, the procedure is preferably carried out in an inertsolvent such as a 1-4C aliphatic alcohol (ethanol or methanol forexample) in the presence of sodium hydrogen carbonate, at a temperatureof between 20° C. and the boiling temperature of the reaction medium.

[0044] In step D, the oxidation is preferably carried out in DMSO, usingthe sulfurtrioxide-pyridine complex, at a temperature close to 20° C. orusing dimethyl sulfoxide, in the presence of oxalyl chloride andtriethylamine, at a temperature of between −70 and −50° C.

[0045] In step E, the procedure is carried out according to the methoddescribed by GRISAR M. et al., in J. Med. Chem., 885 (1973). Themagnesium compound of the brominated derivative is formed and then thenitrile is reacted, in an ether such as ethyl ether, at a temperature ofbetween 0° C. and the boiling temperature of the reaction medium. Afterhydrolysis with an alcohol, the intermediate imine is reduced in situwith sodium borohydride at a temperature of between 0° C. and theboiling temperature of the reaction medium.

[0046] The R₃—CO—R₄ derivatives are commercially available or may beobtained by application or adaptation of the methods described by KUNDERN. G. et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO-MARRASM., Eur. J. Med. Chem., 23 (5) 477 (1988); SKINNER et al., J. Med.Chem., 14 (6) 546 (1971); HURN N. K., Tet. Lett., 36 (52) 9453 (1995);MEDICI A. et al., Tet. Lett., 24 (28) 2901 (1983); RIECKE R. D. et al.,J. Org. Chem., 62 (20) 6921 (1997); KNABE J. et al., Arch. Pharm., 306(9) 648 (1973); CONSONNI R. et al., J. Chem. Soc. Perkin Trans 1, 1809(1996); FR-96-2481 and JP-94-261393.

[0047] The R₃Br derivatives are commercially available or may beobtained by application or adaptation of the methods described byBRANDSMA L. et al., Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIREM. et al., Synth. Comm., 24 (1) 95 (1994); GODA H. et al., Synthesis, 9849 (1992); BAEUERLE P. et al., J. Chem. Soc. Perkin Trans 2, 489(1993).

[0048] The R₄CN derivatives are commercially available or may beobtained by application or adaptation of the methods described byBOUYSSOU P. et al., J. Het. Chem., 29 (4) 895 (1992); SUZUKI N. et al.,J. Chem. Soc. Chem. Comm., 1523 (1984); MARBURG S. et al., J. Het.Chem., 17 1333 (1980); PERCEC V. et al., J. Org. Chem. 60 (21) 6895(1995).

[0049] The compounds of formula (I) for which R represents a chain (B)in which R′ is a hydrogen atom may also be prepared by action of aderivative R₃CH(Br)R₄ (VI) for which R₃ and R₄ have the same meanings asin formula (I) with a derivative of formula:

[0050] in which R₁ and R₂ have the same meanings as in formula (I).

[0051] This reaction is generally carried out in the presence of a basesuch as an alkali metal carbonate (potassium carbonate for example), inan inert solvent such as acetonitrile, at the boiling temperature of thereaction medium.

[0052] The derivatives of formula (VI) are commercially available or maybe obtained by application or adaptation of the method described byBACHMANN W. E., J. Am. Chem. Soc., 2135 (1933). Generally, thecorresponding alcohol R₃CHOHR₄ is brominated using hydrobromic acid, inacetic acid, at a temperature of between 0° C. and the boilingtemperature of the reaction medium.

[0053] The corresponding R₃CHOHR₄ alcohols are commercially available ormay be obtained by application or adaptation of the methods described byPLASZ A. C. et al., J. Chem. Soc. Chem. Comm., 527 (1972).

[0054] The derivatives of formula (VII) may be obtained by hydrolysis ofa derivative of formula:

[0055] in which R₁ and R₂ have the same meanings as in formula (I).

[0056] This reaction is generally carried out using hydrochloric acid,in an inert solvent such as an ether (dioxane for example), at atemperature close to 20° C.

[0057] The derivatives of formula (VIII) are obtained by reacting vinylchloroformate with a corresponding compound of formula (I) for [lacuna]R represents a chain of formula (B), R′ represents a hydroxyl radical,R₃ and R₄ are phenyl radicals, in an inert solvent such as a chlorinatedsolvent (dichloromethane or chloroform for example), at a temperature ofbetween 0° C. and the boiling temperature of the reaction mixture.

[0058] The compounds of formula (I) for which R is a chain (B) in whichR′ is a —CO-alk radical may be prepared by reacting a halide Hal-CO-alkin which Hal represents a halogen atom and, preferably, a chlorine atomand alk represents an alkyl radical with a corresponding compound offormula (I) for which R is a chain (B) in which R′ is a hydrogen atom.

[0059] This reaction is generally carried out in an inert solvent suchas tetrahydrofuran, dioxane, a chlorinated solvent (dichloromethane orchloroform for example), at a temperature of between −50° C. and 20° C.,in the presence of n-butyllithium.

[0060] The compounds of formula (I) for which R₂ represents an aromaticor a heteroaromatic substituted with —NR₆R₇ in which R₆ and R₇ eachrepresent a hydrogen atom may also be prepared by reducing acorresponding compound of formula (I) for which R₂ represents anaromatic or a heteroaromatic substituted with nitro.

[0061] This reaction is carried out by any known method which makes itpossible to reduce a nitro to an amino without affecting the rest of themolecule. Preferably, iron is used in the presence of hydrochloric acidin a 1-4C aliphatic alcohol such as ethanol, at the boiling temperatureof the reaction medium.

[0062] The compounds of formula (I) for which R₂ represents an aromaticor heteroaromatic substituted with —COHNR₉ and/or R₃ and/or R₄ representan aromatic or a heteroaromatic substituted with —CONR₁OR₁₁ may also beprepared by reacting a corresponding compound of formula (I) for whichR₂ and/or R₃ and/or R₄ represent an aromatic or a heteroaromaticsubstituted with —COOR₅ for which R₅ is alkyl or phenyl optionallysubstituted with halogens with respectively an amine H₂NR₉ or HNR₁OR₁₁for which R₉, R₁₀ and R₁₁ have the same meanings as in formula (I).

[0063] This reaction is generally carried out in an inert solvent suchas a chlorinated solvent (dichloromethane or chloroform for example) ora 1-4C aliphatic alcohol (methanol or ethanol for example), at atemperature of between 0° C. and the boiling temperature of the reactionmixture.

[0064] The compounds of formula (I) for which R₂ represents an aromaticsubstituted with hydroxyl and/or R₃ and/or R₄ represent an aromatic or aheteroaromatic substituted with hydroxyl may also be prepared byhydrolysis of a corresponding compound of formula (I) for which R₂represents an aromatic substituted with alkoxy and/or R₃ and/or R₄represent an aromatic or a heteroaromatic substituted with alkoxy.

[0065] This reaction is carried out by any method of hydrolyzing analkoxy to a hydroxyl without affecting the rest of the molecule.Preferably, the hydrolysis is carried out using boron tribromide, in achlorinated solvent such as dichloromethane, at a temperature close to20° C.

[0066] The compounds of formula (I) for which R₂ represents an aromaticsubstituted with —NR₆R₇ for which R₆ represents an alkyl radical and R₇represents a hydrogen atom may also be prepared by deprotecting acorresponding compound of formula (I) for which R₂ represents anaromatic substituted with an —N(alk)COOR₈ in which R₈ represents atert-butyl radical.

[0067] This reaction is generally carried out using hydrochloric acid,in a solvent such as dioxane at a temperature close to 20° C.

[0068] The compounds of formula (I) for which R₂ and/or R₃ and/or R₄represent an aromatic substituted with —COOR₅ may also be prepared byesterification of a derivative of formula:

[0069] for which R represents a chain C═C(SO₂R₁)R₁₂ orC(OR′)CH(SO₂R)R′₂, R₁, R′₂, R′₃ and R′₄ have the same meanings as thesubstituents R₁, R₂, R₃ and R₄ of formula (I) with the proviso that atleast one of the substituents R′₂, R′₃ and R′₄ represents an aromatic ora heteroaromatic substituted with carboxyl, using a derivative offormula R₅OH for which R₅ is alkyl or phenyl optionally substituted withone or more halogens.

[0070] When R₅ is alkyl, this reaction is generally carried out in thepresence of an inorganic acid (sulfuric acid for example), at atemperature of between 20° C. and the boiling temperature of thereaction medium. When R₅ is optionally substituted phenyl, this reactionis preferably carried out in the presence of a carbodiimide(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide orN,N′-dicyclohexylcarbodiimide for example), in an inert solvent such asan imide (dimethylformamide) or a chlorinated solvent (methylenechloride, 1,2-dichloroethane or chloroform for example), at atemperature of between 0° C. and the boiling temperature of the reactionmixture.

[0071] The derivatives of formula (IX) for which R represents a chainC═C(SO₂R₁) R′₂ or C(OR′)CH(SO₂R₁) R′₂, R′, R₁, R′₂, R′₃ and R′₄ have thesame meanings as the substituents R′, R₁, R₂, R₃ and R₄ of the formula(I) with the proviso that at least one of the substituents R′₂, R′₃ andR′₄ represents an aromatic or a heteroaromatic substituted with carboxylmay be obtained according to the methods described above for thepreparation of the compounds of formula (I) from the correspondingintermediates and in particular according to the method described inExample 29.

[0072] The compounds of formula (I) for which R₂ and/or R₃ and/or R₄represent an aromatic or a heteroaromatic substituted withalkylthioalkyl may also be prepared by reaction of a derivative offormula (IX) for which R represents a chain C═C(SO₂R₁)R′₂ orC(OR′)CH(SO₂R₁)R′₂, R′, R₁, R′₂, R′₃ and R′₄ have the same meanings asthe substituents R′, R₁, R₂, R₃ and R₄ of the formula (I) with theproviso that at least one of the substituents R′₂, R′₃ and R′₄represents an aromatic or a heteroaromatic substituted with haloalkylwith sodium alkylthiolate.

[0073] This reaction is generally carried out in an inert solvent suchas an amide (dimethylformamide for example), at a temperature close to20° C.

[0074] The derivatives of formula (IX) for which R represents a chainC═C(SO₂R₁)R′₂ or C(OR′) CH(SO₂R₁)R′₂, R′, R₁, R′₂, R′₃ and R′₄ have thesame meanings as the substituents R′, R₁, R₂, R₃ and R₄ of. the formula(I) with the proviso that at least one of the substituents R′₂, R′₃ andR′₄ represents an aromatic or a heteroaromatic substituted withhaloalkyl may be obtained by reacting a phosphorus trihalide (preferablyphosphorus tribromide) with a corresponding compound of formula (I) forwhich R₂ and/or R₃ and/or R₄ represent an aromatic or a heteroaromaticsubstituted with hydroxyalkyl, in an inert solvent such as a chlorinatedsolvent (carbon tetrachloride or chloroform for example), at atemperature close to 20° C.

[0075] The compounds of formula (I) for which R₂ and/or R₃ and/or R₄represent an aromatic substituted with hydroxyalkyl in which the alkylcontains one carbon atom may also be prepared by reducing a compound offormula (I) for which at least one of the substituents R₂, R₃ and R₄represents an aromatic substituted with formyl.

[0076] This reaction is generally carried out using sodium borohydride,in a 1-4C aliphatic alcohol (methanol or ethanol for example), at atemperature close to 0° C.

[0077] The compounds of formula (I) for which R₃ and/or R₄ represents anaromatic substituted with -alk-NR₆R₇ for which alk is an alkylcontaining one carbon atom may also be prepared by reacting a compoundof formula (I) for which at least one of the substituents R₃ and R₄represents an aromatic substituted with formyl with an amine HNR₆R₇ inwhich R₆ and R₇ have the same meanings as in formula (I).

[0078] This reaction is generally carried out in an inert solvent suchas a chlorinated solvent (dichloroethane for example), at a temperatureclose to 20° C. in the presence of sodium triacetoxyborohydride orsodium cyanoborohydride.

[0079] The compounds of formula (I) for which R₂ represents an aromaticor a heteroaromatic substituted with —CONHR₉ and/or R₃ and/or R₄represents an aromatic or heteroaromatic substituted with —CO—NR₁₀R₁₁may also be prepared by reacting a derivative of formula (IX) for whichR represents a chain C═C(SO₂R₁)R′₂ or C(OR′)CH(SO₂R₁)R₁₂, R′, R₁, R′2R′₃ and R′₄ have the same meanings as the substituents R′, R₁, R₂, R₃and R₄ of the formula (I) with the proviso that at least one of thesubstituents R′₂, R′₃ and R′₄ represents an aromatic or a heteroaromaticsubstituted with carboxyl with respectively an amine H₂NR₉ or HNR₁₀R₁₁in which R₉, R₁₀ and R₁₁ have the same meanings as in formula (I).

[0080] This reaction is preferably carried out in the presence of acondensing agent which is used in peptide chemistry such as acarbodiimide (for example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimideor N,N′-dicyclohexylcarbodiimide) or N,N′-carbonyldiimidazole, in aninert solvent such as an ether (tetrahydrofuran or dioxane for example),an amide (dimethylformamide) or a chlorinated solvent (methylenechloride, 1,2-dichloroethane or chloroform for example) at a temperatureof between 0° C. and the boiling temperature of the reaction mixture, orafter prior binding of the acid to a resin of the TFP type of formula:

[0081] in which S represents an aminopolystyrene resin, in an inertsolvent such as dimethylformamide, in the presence of4-dimethylaminopyridine, at a temperature close to 20° C. The binding tothe resin is generally carried out in dimethylformamide, in the presenceof 4-dimethylaminopyridine and 1,3-diisopropyl-carbodiimide, at atemperature close to 20° C.

[0082] The compounds of formula (I) for which R₂ and/or R₃ and/or R₄,represent an aromatic or a heteroaromatic substituted with —CO—NH—NR₆R₇may also be prepared by reacting a corresponding compound of formula (I)for which R₂ and/or R₃ and/or R₄ represent an aromatic or aheteroaromatic substituted with —COOR₅ and R₅ represents an alkyl orphenyl radical optionally substituted with halogens, with a hydrazineH₂N—NR₆R₇ for which R₆ and R₇ have the same meanings as in formula (I).

[0083] This reaction is generally carried out in an inert solvent suchas dimethylformamide, at a temperature close to 20° C.

[0084] The compounds of formula (I) for which R₂ represents an aromaticor a heteroaromatic substituted with —CO—NHR₉ in which R₉ represents ahydrogen atom and/or R₃ and/or R₄ represent an aromatic or aheteroaromatic substituted with —CO—NR₁₀R₁₁ in which R₁₀ and R₁ arehydrogen atoms may also be prepared by hydrolysis of a correspondingcompound of formula (I) for which R₂ and/or R₃ and/or R₄ represent anaromatic or a heteroaromatic substituted with cyano.

[0085] This reaction is carried out by any known method which makes itpossible to pass from a nitrile to the corresponding carbamoyl withoutaffecting the rest of the molecule. Preferably, the procedure is carriedout using hydrochloric acid, in acetic acid, at a temperature close to20° C.

[0086] The compounds of formula (I) for which R₂ represents an aromaticsubstituted with —O-alk-NR₁₂R₁₃ may also be prepared by reacting aderivative of formula (IX) for which R represents a chain C═C(SO₂R₁)—R′₂or C(OR′)CH(SO₂R₁)R₁₂, R′, R₁, R₂′, R₃′ and R₄′have the same meanings asthe substituents R′, R₁, R₂, R₃ and R₄ of the formula (I) with theproviso that at least one of the substituents R₂′, R₃ or R₄ representsan aromatic substituted with —O-alk-Hal in which alk represents an alkylradical and Hal represents a halogen atom and, preferably, a chlorine orbromine atom, with an amine HNRL₂R₁₃ in which R₁₂R₁₃ have the samemeanings as in formula (I).

[0087] This reaction is generally carried out in an inert solvent suchas acetonitrile, in the presence of an alkali metal carbonate (potassiumcarbonate for example), at a temperature close to 20° C.

[0088] The derivatives of formula (IX) for which R represents a chainC═C(SO₂R₁) R₁₂ or C(OR′) CH(SO₂R₁) R′₂, R′, R₁, R₂′, R₃′ and R₄′ havethe same meanings as the substituents R′, R₁, R₂, R₃ and R₄ of theformula (I) with the proviso that at least one of the substituents R₂′,R₃′ or R₄′ represents an aromatic substituted with —O-alk-Hal in whichalk represents an alkyl radical and Hal represents a halogen atom may beobtained by reacting a corresponding compound of formula (I) for whichR₂ represents an aromatic substituted with hydroxide with a Hal-alk-Halderivative in which Hal represents a halogen.

[0089] This reaction is generally carried out in an inert solvent suchas a ketone (methyl ethyl ketone for example), in the presence of a basesuch as an alkali metal carbonate (potassium carbonate for example), atthe boiling temperature of the reaction medium.

[0090] The compounds of formula (I) for which R₃ and/or R₄ represents anaromatic substituted with -alk-NR₆R₇ may also be prepared by reacting aderivative of formula (IX) for which R represents a chain C═C(SO₂R₁)R₁₂or C(OR′) CH(SO₂R₁) R′₂, R′, R₁, R₂′, R₃′ and R₄ ¹ have the samemeanings as the substituents R′, R₁₁ R₂, R₃ and R₄ of the formula (I)with the proviso that at least one of the substituents R₃′ or R₄′represents a substituted aromatic -alk-Cl in which alk represents analkyl radical with an amine HNR₆R₇ in which R₆R₇ have the same meaningsas in formula (I).

[0091] This reaction is generally carried out in an inert solvent suchas a chlorinated solvent (dichloromethane for example), optionally inthe presence of a nitrogen base such as dimethylaminopyridine,diisopropylethylamine, at a temperature of between 5 and 25° C.

[0092] The derivatives of formula (IX) in which R represents a chainC═C(SO₂R₁)R′₂ or C(OR′) CH(SO₂R₁) R₂, R′, R₁, R₂′, R₃′ and R₄′ have thesame meanings as the substituents R′, R₁, R₂, R₃ and R₄ of the formula(I) with the proviso that at least one of the substituents R₃′ or R₄′represents an aromatic substituted with -alk-Cl may be obtained byreacting thionyl chloride with a corresponding compound of formula (I)for which at least one of the substituents R₃ or R₄ represents anaromatic substituted with one or more hydroxyalkyl radicals.

[0093] This reaction is generally carried out in an inert solvent suchas a chlorinated solvent (dichloromethane for example), at a temperatureof between 10 and 30° C.

[0094] The compounds of formula (I) for which R represents a chain B, R′represents a hydrogen atom and R₃ and/or R₄ represents an aromaticsubstituted with hydroxyalkyl in which the alkyl residue contains onecarbon atom may also be prepared by reacting diisobutylaluminum hydridewith a corresponding compound of formula (I) for which R represents achain B, R′ represents a hydrogen atom and R₃ and/or R₄ represents anaromatic substituted with one or more —COOR₅ radicals, in which R₅ is analkyl radical.

[0095] This reaction is generally carried out in toluene, at atemperature of between −30° C. and 0° C.

[0096] The compounds of formula (I) for which R₂ represents a phenylradical substituted with —NR₆R₇ representing a 1-piperazinyl ringsubstituted at the 4 position with an alkyl radical may also be preparedby reacting a corresponding compound of formula (I) for which R₂represents a phenyl radical substituted with a radical —NR₆R₇representing a 1-piperazinyl ring with an alk-CHO derivative in whichalk represents a straight- or branched-chain alkyl radical containing 1to 5 carbon atoms.

[0097] This reaction is generally carried out in an inert solvent suchas a chlorinated solvent (dichloroethane or chloroform for example), inthe presence of NaBH(OCOCH₃)₃, at a temperature close to 20° C.

[0098] The compounds of formula (I) for which R₂ represents a phenylradical substituted with —NR₆R₇ representing a 1-piperazinyl ringsubstituted at the 4 position with a radical —COOalk may also beprepared by reacting a corresponding compound of formula (I) for whichR₂ represents a phenyl radical substituted with a radical —NR₆R₇representing a 1-piperazinyl ring with a derivative of formulaHal-COOalk in which alk represents an alkyl radical and Hal represents ahalogen atom and, preferably, a chlorine atom.

[0099] This reaction is generally carried out in pyridine, at atemperature close to 20° C.

[0100] The compounds of formula (I) for which R₂ represents a phenylradical substituted with —NR₆R₇ representing a 1-piperazinyl ringsubstituted at the 4 position with a radical —CO—NHalk or —CS—NHalk mayalso be prepared by reacting a corresponding compound of formula (I) forwhich R₂ represents a phenyl radical substituted with —NR₆R₇representing a 1-piperazinyl ring with a derivative of formula Y═C═Nalkin which alk represents a straight- or branched-chain alkyl radicalcontaining 1 to 6 carbon atoms and Y represents a sulfur or oxygen atom.

[0101] This reaction is generally carried out in an inert solvent suchas a chlorinated solvent (dichloromethane for example), at a temperatureclose to 20° C.

[0102] The compounds of formula (I) for which R₂ represents a phenylradical substituted with a radical —NR₆R₇ representing a 1-piperazinylring substituted at the 4 position with a radical —CO-alk-NR₁₄R₁₅ mayalso be prepared by reacting a corresponding compound of formula (I) forwhich R₂ represents a phenyl radical substituted with a radical —NR₆R₇representing a 1-piperazinyl ring with an acid of formulaR₁₅R₁₄N-alk-COOH in which alk represents an alkyl radical and R₁₄ andR¹⁵ have the same meanings as in formula (I), optionally followed bydeprotection of the product for which R₁₄ is a tert-butoxycarbonylradical in order to obtain the compounds for which R₁₄ is a hydrogenatom.

[0103] This reaction is generally carried out in an inert solvent suchas a chlorinated solvent (dichloroethane for example), at a temperatureclose to 20° C. The deprotection is carried out using formic acid at atemperature close to 20° C.

[0104] The compounds of formula (I) for which R₂ represents a phenylradical substituted with a radical —NR₆R₇ representing a 1-piperazinylring substituted at the 4 position with a radical —CO-alk in which alkrepresents a methyl radical may also be prepared by reacting acorresponding compound of formula (I) for which R₂ represents a phenylradical substituted with a radical —NR₆R₇ representing a 1-piperazinylring with acetic anhydride.

[0105] This reaction is generally carried out in the presence ofpyridine, at a temperature close to 20° C.

[0106] It is understood for persons skilled in the art that, to carryout the processes according to the invention which are described above,it may be necessary to introduce groups protecting amino, hydroxyl andcarboxyl functions in order to avoid side reactions. These groups arethose which allow removal without affecting the rest of the molecule. Asexamples of groups protecting the amino function, there may be mentionedtert-butyl or methylcarbamates which may be regenerated usingiodotrimethylsilane or allyl using palladium catalysts. As examples ofgroups protecting the hydroxyl function, there may be mentionedtriethylsilyl and tert-butyldimethylsilyl which may be regenerated usingtetrabutylammonium fluoride or alternatively asymmetric acetals(methoxymethyl or tetrahydropyranyl for example) with regeneration usinghydrochloric acid. As groups protecting carboxyl functions, there may bementioned esters (allyl or benzyl for example), oxazoles and2-alkyl-1,3-oxazolines. Other protecting groups which can be used aredescribed by GREENE T. W. et al., Protecting Groups in OrganicSynthesis, second edition, 1991, John Wiley & Sons.

[0107] The compounds of formula (I) may be purified by the customaryknown methods, for example by crystallization, chromatography orextraction.

[0108] The enantiomers of the compounds of formula (I) may be obtainedby resolution of the racemates for example by chromatography on a chiralcolumn according to PIRCKLE W. H. et al., Asymmetric synthesis, Vol. 1,Academic Press (1983) or by formation of salts or by synthesis fromchiral precursors. The diastereoisomers may be prepared according toknown conventional methods (crystallization, chromatography or fromchiral precursors).

[0109] The compounds of formula (I) may be optionally converted toaddition salts with an inorganic or organic acid by the action of suchan acid in an organic solvent such as an alcohol, a ketone, an ether ora chlorinated solvent. These salts also form part of the invention.

[0110] As examples of pharmaceutically acceptable salts, the followingsalts may be mentioned: benzenesulfonate, hydrobromide, hydrochloride,citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate,maleate, methane sulfonate, methylene-bis-S-oxynaphtoate, nitrate,oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate,theophyllineacetate and p-toluenesulfonate.

[0111] The compounds of formula (I) exhibit advantageous pharmacologicalproperties. These compounds possess a high affinity for the cannabinoidreceptors and particularly those of the CB1 type. They are CBI receptorantagonists and are therefore useful in the treatment and prevention ofdisorders affecting the central nervous system, the immune system, thecardiovascular or endocrine system, the respiratory system, thegastrointestinal apparatus and reproductive disorders (Hollister, Pharm.Rev.; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114(1991), Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology andNeurophysiology, 459, Murphy L. and Barthe A. Eds, CRC Press, 1992) ofbacterial, viral and parasitic infections.

[0112] Accordingly, these compounds may be used for the treatment orprevention of psychoses including schizophrenia, anxiety disorders,depression, epilepsy, neurodegeneration, cerebellar and spinocerebellardisorders, cognitive disorders, cranial trauma, panic attacks,peripheral neuropathies, glaucomas, migraine, Parkinson's disease,Alzeimer's disease, Huntington's chorea, Raynaud's syndrome, tremor,obsessive-compulsive disorder, senile dementia, thymic disorders,Tourette's syndrome, tardive dyskinesia, bipolar disorders, cancers,movement disorders induced by medicaments, dystonia, endotoxemic shocks,hemorrhagic shocks, hypotension, insomnia, immunological diseases,multiple sclerosis, vomiting, asthma, appetite disorders (bulimia,anorexia), obesity, memory disorders, in weaning from chronic treatmentsand alcohol or drug abuse (opiods, barbiturates, cannabis, cocaine,amphetamine, phencyclide, hallucinogens, benzodiazepines for example),as analgesics or potentiators of the analgesic activity of the narcoticand normarcotic drugs. They may also be used for the treatment orprevention of intestinal transit disorders, as antibacterial, antiviraland antiparasitic agents.

[0113] The affinity of the compounds of formula (I) for the cannabisreceptors has been determined according to the method described byKUSTER J. E., STEVENSON J. I., WARD S. J., D'AMBRA T. E., HAYCOCK D. A.in J. Pharmacol. Exp. Ther., 264 1352-1363 (1993).

[0114] In this test, the IC₅₀ of the compounds of formula (I) is lessthan or equal to 100 nM.

[0115] Their antagonist activity has been shown by means of the model ofhypothermia induced by an agonist of the cannabis receptors (CP-55940)in mice, according to the method described by Pertwee R. G. inMarijuana, Harvey D. J. eds, 84 Oxford IRL Press, 263-277 (1985).

[0116] In this text the ED50 of the compounds of formula (I) is lessthan or equal to 50 mg/kg.

[0117] The compounds of formula (I) exhibit low toxicity. Their LD₅₀ isgreater than 40 mg/kg by the subcutaneous route in mice.

[0118] The preferred compounds of formula (I) are those for which

[0119] R represents a chain (A) or (B) and R′represents a hydrogen atomor a —COalk radical,

[0120] R₁ represents a methyl or ethyl radical,

[0121] R₂ represents either an aromatic chosen from phenyl and naphthyl,these aromatics being nonsubstituted or substituted with one or morehalogens, alkyl, alkoxy, hydroxyl, —COORs, trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇, —CO—NH—NR₆R₇, cyano,—CONHR₉ alkylsulfanyl, hydroxyalkyl, nitro, —CO—NR₁₆R₁₇, —O-alkNR₁₂R₁₃or alkylthioalkyl or a heteroaromatic chosen from isoquinolyl, pyridyl,quinolyl, 1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl andthienyl, these heteroaromatics being unsubstituted or substituted with ahalogen, alkyl, alkoxy, —COOR₅, trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇, —CO—NH—NR₆R₇, cyano,—CONHR₉, alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkyl,

[0122] R₃ and R₄, which are identical or different, represent either anaromatic chosen from phenyl or naphthyl, these aromatics beingnonsubstituted or substituted with one or more halogens, alkyl, alkoxy,trifluoromethyl, trifluoromethoxy, —CONR₁₀R₁₁, -alk-NR₆R₇ hydroxyalkyl,formyl or —COOR₅, or a heteroaromatic chosen from thiazolyl or thienylrings, these heteroaromatics being unsubstituted or substituted with ahalogen, alkyl, alkoxy, —CONR₁₀R₁₁, -alk-NR₆R₇, hydroxyalkyl or —COOR₅.

[0123] R₅ is alkyl or phenyl which is optionally substituted with one ormore halogens,

[0124] R₆ and R₇, which are identical or different, represent a hydrogenatom or an alkyl, —COOalk, cycloalkyl, alkylcycloalkyl,-alk-O-alk orhydroxyalkyl radical or alternatively R₆ and R₇ together form with thenitrogen atom to which they are attached a 3- to 10-membered saturatedor unsaturated mono- or bicyclic heterocycle optionally containinganother heteroatom chosen from oxygen, sulfur and nitrogen and beingoptionally substituted with one or more alkyl, —COalk, —COOalk,—CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo, hydroxyalkyl, alk-O-alk or—CO—NH₂ radicals,

[0125] R₉ represents a hydrogen atom or an alkyl radical or an alkylradical substituted with dialkylamino, phenyl, cycloalkyl (optionallysubstituted with —COOalk) or a 3- to 10-membered saturated orunsaturated mono- or bicyclic heterocycle optionally containing one ormore heteroatoms chosen from oxygen, sulfur and nitrogen and beingoptionally substituted with one or more alkyl radicals,

[0126] R₁₀ and R₁₁, which are identical or different, represent ahydrogen atom or an alkyl radical or alternatively R₁₀ and R₁₁ togetherform with the nitrogen atom to which they are attached a 3- to10-membered saturated mono- or bicyclic heterocycle optionallycontaining another heteroatom chosen from oxygen, sulfur and nitrogenand being optionally substituted with an alkyl radical,

[0127] R₁₂ and R₁₃, which are identical or different, represent ahydrogen atom or an alkyl or cycloalkyl radical or alternatively R₁₂ andR₁₃ together form with the nitrogen atom to which they are attached a 3-to 10-membered saturated mono- or bicyclic heterocycle optionallycontaining another heteroatom chosen from oxygen, sulfur and nitrogenand being optionally substituted with an alkyl, —COalk, —COOalk,—CO—NHalk, —CS—NHalk or —CO-alk-NR₁₄R₁₅ radical or a 3- to 10-memberedsaturated mono- or bicyclic heterocycle containing a heteroatom chosenfrom oxygen, sulfur and nitrogen,

[0128] R₁₄ and R₁₅, which are identical or different, represent ahydrogen atom or an alkyl or —COOalk radical, R₁₆ and R₁₇ together formwith the nitrogen atom to which they are attached a 3- to 10-memberedsaturated mono- or bicyclic heterocycle optionally containing anotherheteroatom chosen from oxygen, sulfur and nitrogen, alk represents analkyl or alkylene radical, their optical isomers and their salts with aninorganic or organic acid.

[0129] The compounds of formula (I) which are particularly preferred arethose for which

[0130] R represents a chain (A) or (B),

[0131] R′ representing a hydrogen atom or a radical —COalk,

[0132] R₁ represents a methyl or ethyl radical,

[0133] R₂ represents either an aromatic chosen from

[0134] naphthyl,

[0135] phenyl,

[0136] phenyl substituted with one or more halogen, alkyl, alkoxy,hydroxyl, —COOR₅, (in which R₅, represents an alkyl or phenyl radicaloptionally substituted with several halogens) trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇ (in which R₆ and R₇,which are identical or different, represent a hydrogen atom or an alkylor —COOalk radical or alternatively R₆ and R₇ together form with thenitrogen atom to which they are attached a heterocycle chosen from

[0137] pyrrolidinyl, piperidyl, piperazinyl or piperazinyl substitutedwith one or more alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk or—CO-alk-NR₁₄R₁₅ radicals, in which R₁₄ and R₁₅, which are identical ordifferent, represent a hydrogen atom or an alkyl radical), —CO—NH—NR₆R₇(R₆ and R₇, which are identical or different, represent a hydrogen atomor an alkyl radical or alternatively R₆ and R₇ together form with thenitrogen atom to which they are attached a heterocycle chosen frompiperidyl, piperazinyl or piperazyl substituted with one or more alkylradicals), cyano, —CONHR₉ (in which R₉ represents a hydrogen atom or analkyl radical or an alkyl radical substituted with dialkylamino, phenyl,cycloalkyl (optionally substituted with —COOalk) or a heterocycle chosenfrom pyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl,or morpholinyl), alkylsulfanyl, hydroxyalkyl, nitro, —CO—NR₁₆R₁₇, (inwhich R₁₆ and R₁₇ together form with the nitrogen atom to which they areattached a piperidyl ring), —O-alkNR₁₂R₁₃ (in which R₁₂ and R₁₃ togetherform with the nitrogen atom to which they are attached a morpholinoring) or alkylthioalkyl,

[0138] or a heteroaromatic chosen from

[0139] isoquinolyl,

[0140] pyridyl,

[0141] quinolyl,

[0142] 1,2,3,4-tetrahydroisoquinolyl,

[0143] 1,2,3,4-tetrahydroquinolyl,

[0144] thienyl, or

[0145] thienyl substituted with a —COOR₅ (in which R₅ represents analkyl radical) or —CONHR₉, (in which R₉ represents an alkyl radical),

[0146] R₃ and R₄, which are identical or different, represent either anaromatic chosen from

[0147] phenyl or

[0148] phenyl substituted with one or more halogen, alkyl, alkoxy,trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl, —COOR₅ (inwhich R₅ is an alkyl radical), —CONR₁₀R₁₁ (in which R₁₀ and R₁₁, whichare identical or different, represent a hydrogen atom or an alkylradical), -alk-NR₆R₇ (in which R₆ and R₇, which are identical ordifferent, represent a hydrogen atom or an alkyl, cycloalkyl, -alk-O-alkor hydroxyalkyl radical or alternatively R₆ and R₇ together form withthe nitrogen atom to which they are attached a heterocycle chosen frompiperidyl (optionally substituted with alkyl or oxo), pyrrolidinyl(optionally substituted with alkyl, hydroxyalkyl, -alk-O-alk or—CO—NH₂), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl optionallysubstituted with oxo, alkyl, hydroxyalkyl, —COOR₅ (in which R₅ is analkyl radical),

[0149] or a heteroaromatic chosen from

[0150] thiazolyl or

[0151] thienyl,

[0152] alk represents an alkyl or alkylene radical,

[0153]  their optical isomers and their salts with an inorganic ororganic acid.

[0154] Preferably, R₂ is a substituted phenyl radical, the latter ismonosubstituted and, in particular, at the 3-position or alternativelydisubstituted and, in particular at the 3,5, 2,5 or 2,3-positions.

[0155] Preferably, when R₃ is a substituted phenyl radical, the latteris monosubstituted and, in particular, at the 4-position ordisubstituted and, in particular, at the 2,4-positions.

[0156] Preferably, when R₄ is a substituted phenyl radical, the latteris monosubstituted and, in particular, at the 4-position ordisubstituted and, in particular, at the 2,4-positions.

[0157] The following compounds may be mentioned among the preferredcompounds:

[0158] 1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]-azetidine,

[0159]1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,

[0160]1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)-methylene]azetidine,

[0161]1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)-methylene]azetidine,

[0162]1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)-methylene]azetidine,

[0163]1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)-methylene]azetidine,

[0164]1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0165]1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0166]1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)-methylene]azetidine,

[0167]1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)-methylene]azetidine,

[0168]1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxy-phenyl)methylene]azetidine,

[0169]1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethyl-phenyl)methylene]azetidine,

[0170]1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl]-(methylsulfonyl)methylene}azetidine,

[0171]1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)-methylene]azetidine,

[0172]1-benzhydryl-3-[(3-methoxycarbonylphenyl)-(methylsulfonyl)methylene]azetidine,

[0173]1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)-methylene]azetidine,

[0174]1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)-methylene]azetidine,

[0175]1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)-methylene]azetidine,

[0176]1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)-(methylsulfonyl)methylene]azetidine,

[0177]1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0178]1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0179]1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0180](RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,

[0181](R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,

[0182](S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl)]azetidine,

[0183]1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,

[0184]1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl(methylsulfonyl)methylene]azetidine,

[0185]1-[bis(4-chlorophenyl)methyl]-3-{[(3,5-bis-(trifluoromethyl)phenyl]methylsulfonylmethylene}-azetidine,

[0186](RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,

[0187](R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,

[0188](S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,

[0189](RS)-1-{(4-chlorophenyl)[4-hydroxymethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0190](R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0191](S)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0192](RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0193](R)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0194](S)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0195]1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0196]1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0197]1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0198]1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0199]1-{(R)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0200]1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0201]1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0202]1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0203]1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0204]1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0205]1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonyl-piperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0206]1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonyl-piperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0207]1-{(RS)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0208]1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0209]1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0210]1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0211]1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0212]1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)-phenyl]methyl}-3-(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0213]1-{{(RS)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)amino-methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0214]1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)amino-methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0215]1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)amino-methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0216]1-{(RS)-(4-chlorophenyl)[4-(di-n-propylamino-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0217]1-{(R)-(4-chlorophenyl)[4-(di-n-propylamino-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0218]1-{(S)-(4-chlorophenyl)[4-(di-n-propylamino-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0219]1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0220]1-{(R)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0221]1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0222]1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0223]1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0224]1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0225]1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0226]1-{(R)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0227]1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0228]1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0229]1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0230]1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0231]1-{(RS)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0232]1-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0233]1-{(S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0234]1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0235]1-{(R)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0236]1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,

[0237](RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0238](R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0239](S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0240](RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0241](R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0242](S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,

[0243](RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,

[0244](R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,

[0245](S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,

[0246]1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)-(methylsulfonyl)methylene]azetidine,

[0247]1-benzhydryl-3-[(3-methylsulfanylphenyl)-(methylsulfonyl)methylene]azetidine,

[0248]1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)]-(methylsulfonyl)methylene]azetidine,

[0249]1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)-(methylsulfonyl)methylene]azetidine,

[0250]1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)-(methylsulfonyl)methylene]azetidine,

[0251]1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)-(methylsulfonyl)methylene]azetidine,

[0252]1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)-(methylsulfonyl)methylene]azetidine,

[0253]1-[bis(4-chlorophenyl)methyl]-3-[(3-methylsulfonyl)-(3-pyrrolidinylphenyl)methylene]azetidine,

[0254]1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethyl-phenyl)(methylsulfonyl)methylene]azetidine,

[0255]1-[bis(4-chlorophenyl)methyl]3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidine,

[0256]1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)-methylene]azetidine,

[0257]1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0258]1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0259]1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0260](RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,

[0261](R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,

[0262](S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,

[0263](RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0264](R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0265](S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0266] 1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]-azetidine,

[0267]1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamoyl]phenyl}(methylsulfonyl)-methylene]azetidine,

[0268]1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)phenyl](methylsulfonyl)-methylene}azetidine,

[0269]1-[bis(thien-2-yl)methyl]-3-[3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,

[0270]1-[bis(p-tolyl)methyl]-3-[(methylsulfonyl)(phenyl)-methylene]azetidine,

[0271]1-[4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,

[0272]1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)-(methylsulfonyl)methylene]azetidine,

[0273](RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0274](R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0275](S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0276]1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine,

[0277]1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methyl-sulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine(RS),1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutyl-aminocarbonylthien-5-yl)(methylsulfonyl)-methylene]azetidine,

[0278]1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonyl-phenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol,

[0279]1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(pyridin-4-yl)methyl-(RS)azetidin-3-ol,

[0280]1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(pyridin-3-yl)methyl-(RS)azetidin-3-ol,

[0281]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-morpholin-4-yl-propyl)benzamide,

[0282]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-dimethylaminopropyl)-benzamide,

[0283]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)-benzamide,

[0284]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide,

[0285]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-piperidin-1-ylbenzamide,

[0286]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-isobutylbenzamide,

[0287]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)-benzamide,

[0288]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylaminoethyl)-benzamide,

[0289]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid N′-methylhydrazide,

[0290]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide,

[0291]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,

[0292]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide,

[0293]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclohexylmethylbenzamide,

[0294]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclopropylmethylbenzamide,

[0295]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-methylbutyl)benzamide,

[0296]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-phenylpropyl)benzamide,

[0297]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,

[0298]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide,

[0299]3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide,

[0300]4-{[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylic acid methyl ester,

[0301]2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl]methyl]-azetidin-3-ylidene}methanesulfonyl-methyl)phenyl]piperazin-1-yl}ethanone,

[0302](2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamicacid tert-butyl ester,

[0303]1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone,

[0304](2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester,

[0305]4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioicacid N-methylamide,

[0306]4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid N-methylamide,

[0307]4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid methyl ester,

[0308]1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine,

[0309]1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-ethylpiperazine,

[0310] 4-acetyl1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,

[0311]1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone,

[0312]1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,

[0313]4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester,

[0314]1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0315]3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidine,

[0316](RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)-methanesulfonylmethylene]azetidin-1-yl}methyl)-benzyl]morpholine,

[0317]4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methane-sulfonylmethyl]phenoxy}butyl)morpholine,

[0318]4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholine,

[0319] their optical isomers and their esters.

[0320] Among these compounds, the following compounds are particularlypreferred;

[0321]1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,

[0322]1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene(RS)]azetidin-3-ol,

[0323]3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methyl-sulfonylmethyl(RS)]azetidine

[0324] their optical isomers and their salts with an inorganic ororganic acid.

[0325] The following examples illustrate the invention without limitingit.

EXAMPLE 1

[0326] 0.3 cm³ of methanesulfonyl chloride is added to a solution of 1 gof 1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol in10 cm³ of pyridine, cooled to 5° C. The mixture is stirred for 2 hoursat 5° C. and then 1 g of 4-dimethylaminopyridine is added in 10 cm³ ofdichloromethane at 5° C. The solution is stirred for 15 hours at roomtemperature and then concentrated to a dryness under reduced pressure(2.7 kPa). The residue obtained is chomatographed on a silica gel column(particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm), eluting at anitrogen pressure of 0.5 bar with dichloromethane and collecting 80 cm³fractions. Fractions 17 to 20 are combined and then concentrated todryness under reduced pressure (2.7 kPa). The residue is crystallizedfrom 10 cm³ of ethyl ether. 0.14 g of1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]azetidine is obtainedmelting at 210° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz):2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s,NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.),between 7.40 and 7.60 (9H, m, 9 CH arom.)].l-Benzhydryl-3-[(methylsulfonyl)(phenyl)-methyl-(RS)]azetidin-3-ol maybe obtained in the following manner: 6.25 cm³ of 1.6 N n-butyllithium insolution in hexane are added to a solution of 1.4 cm³ ofdiisopropylamine in 10 cm³ of tetrahydrofuran, under an argonatmosphere, cooled to 0° C. , and then the mixture is cooled to −70° C.A mixture of 1.7 g of benzyl methyl sulfone in 30 cm³ of tetrahydrofuranare then added and the stirring is maintained for 45 minutes at −70° C.2.4 g of 1-benzhydrylazetidin-3-one are added and then the mixture isstirred for 20 minutes while allowing the mixture to return to roomtemperature. The reaction mixture is filtered and then concentrated todryness under reduced pressure (2.7 kPa). The residue is taken up in 50cm³ of ethyl acetate, 30 cm³ of water and 20 cm³ of normal hydrochloricacid. The precipitate is filtered, washed with 30 cm³ of distilledwater, drained and dried. 2 g of1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol areobtained melting at 260° C.

[0327] 1-Benzhydrylazetidin-3-one may be prepared according to theprocedure described by KATRITZKY A. R. et al. in J. Heterocycl. Chem.,271 (1994).

EXAMPLE 2

[0328] On carrying out the operation according to the procedure ofExample 1 starting with 1.9 g of1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.52 cm³ of methanesulfonyl chloride and 1.7 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 17 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a dichloromethane and ethanol mixture (98.5/1.5by volume) as eluents and collecting 100 cm³ fractions. Fractions 5 and6 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from 2 cm³ of dichloromethaneand 20 cm³ of diisopropyl ether. 0.9 g of1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 180° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.35 (3H, s, PhCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂),4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.20 (5H, m, 5CH arom.), 7.30(5H, t, J=7 Hz, 5CH arom.), 7.50 (4H, d, J=7 Hz, 4 CH arom.)].

[0329]1-Benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.8 g ofmethyl(3-methylbenzyl)sulfone and 3.6 g of 1-benzhydrylazetidin-3-one,2.6 g of a solid are obtained after purification on a silica gel column(particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm) at a nitrogenpressure of 0.5 bar with a dichloromethane and ethanol mixture (98.5/1.5by volume) as eluent. The solid is taken up in 25 cm³ of diisopropylether. After filtration, draining and drying, 1.9 g of1-benzhydryl-3-[(3-methylphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained melting at 170° C.

[0330] Methyl(3-methylbenzyl)sulfone may be prepared in the followingmanner: 10.5 g of oxone^(R) and then 2.6 g ofmethyl(3-methylbenzyl)sulfide and 30 cm³ of ethanol are added, at roomtemperature, to a solution of 30 cm³ of water, 30 cm³ of acetic acid and15 cm³ of 36 N sulfuric acid. The mixture is stirred for 48 hours atroom temperature and then taken up in 100 cm³ of water and 100 cm³ ofethyl acetate. The organic phase is washed with a saturated aqueoussodium bicarbonate solution, decanted off, dried over magnesium sulfateand concentrated to dryness under reduced pressure (2.7 kPa). 2.8 g ofmethyl(3-methylbenzyl)sulfone are obtained in the form of a gum.

[0331] Methyl(3-methylbenzyl)sulfide may be prepared in the followingmanner: 1.7 g of sodium methylthiolate are added, while the temperatureis kept below 30° C. , to a solution of 3.7 g of 3-methylbenzyl bromidein 25 cm³ of dimethylformamide. The mixture is stirred for 2 hours at atemperature close to 20° C. and then taken up in 50 cm³ of ethylacetate. The organic phase is washed with 3 times 100 cm³ of water,dried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). 2.6 g of methyl(3-methyl-benzyl)sulfide are obtainedin the form of an oil.

EXAMPLE 3

[0332] 0.3 cm³ of methanesulfonyl chloride is added to a solution of 3.3g of1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olin 10 cm³ of pyridine, cooled to 5° C. The mixture is stirred for 2hours at 5° C. and then 1 g of 4-dimethylaminopyridine is added in 10cm³ of dichloromethane at 5° C. The solution is stirred for 15 hours atroom temperature and then concentrated to dryness under reduced pressure(2.7 kPa). The residue obtained is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 25 cm),eluting at a nitrogen pressure of 0.5 bar with dichloromethane andcollecting 80 cm³ fractions. Fractions 17 to 20 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 30 cm³ of acetonitrile. 0.14 g of1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 210° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.30 (3H, s, PhCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂),4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30(6H, t, J=7 Hz, 6CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].

[0333]1-Benzhydryl-3-[(4-methylphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g ofmethyl(4-methylbenzyl)sulfone and 5.1 g of 1-benzhydrylazetidin-3-one, 3g of1-benzhydryl-3-[(4-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained melting at 226° C.

[0334] Methyl(4-methylbenzyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.5 g of methyl(4-methylbenzyl)sulfide and 12.3g of oxone^(R), 3.5 g of methyl(4-methylbenzyl)sulfone are obtained inthe form of a solid.

[0335] Methyl(4-methylbenzyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5.6 g of 4-methylbenzyl bromide and 2.3 g ofsodium methylthiolate, 4.7 g of methyl(4-methylbenzyl)sulfide areobtained in the form of a solid.

EXAMPLE 4

[0336] 0.7 cm³ of methanesulfonyl chloride and then 3.8 g of4-dimethylaminopyridine are added to a solution of 3.3 g of1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olin 50 cm³ of dichloromethane, at room temperature. The solution isstirred for 3 hours under reflux and then taken up in twice 50 cm³ ofwater. The organic phase is decanted off, dried and concentrated todryness under reduced pressure (2.7 kPa). The residue obtained ischromatographed on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm), eluting at a nitrogen pressure of 0.5 barwith dichloromethane and then with a dichloromethane and ethanol mixture(99/1 by volume mixture) and collecting 100 cm³ fractions. Fractions 6to 17 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). The solid obtained is crystallized from 50 cm³ ofethyl ether. 2.6 g of1-benzhydryl-3-[(2-methylphenyl)-(methylsulfonyl)methylene]azetidine areobtained in the form of a foam [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 2.30 (3H, s, PhCH₃), 2.95 (3H, s, SCH₃), 3.50 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.70 (1H, s, NCH) between 7.10 and 7.35 (10H,m, 10CH arom.), 7.45 (4H, m, 4CH arom.)].

[0337]1-Benzhydryl-3-[(2-methylphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.4 g ofmethyl(2-methylbenzyl)sulfone and 4.3 g of 1-benzhydrylazetidin-3-one,3.4 g of1-benzhydryl-3-[(2-methylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained melting at 218° C.

[0338] Methyl(2-methylbenzyl)sulfone may be prepared in the followingmanner: by carrying out the operation according to the procedure ofExample 2 starting with 4.5 g of methyl(2-methylbenzyl)sulfide and 16.2g of oxone^(R), 3.4 g of methyl(2-methylbenzyl)sulfone are obtained inthe form of a solid.

[0339] Methyl(2-methylbenzyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 but starting with 5.6 g of 2-methylbenzyl bromide and 2.1 g ofsodium methylthiolate, 4.5 g of methyl(2-methylbenzyl)-sulfide areobtained in the form of a solid.

EXAMPLE 5

[0340] On carrying out the operation according to the procedure ofExample 4 but starting with 2.1 g of1-benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.55 cm³ of methanesulfonyl chloride and 2.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 12to 18 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 3 cm³ ofdichloromethane and 40 cm³ of ethyl ether. 1.1 g of1-benzhydryl-3-[(2-chlorophenyl)-(methylsulfonyl)methylene]azetidine areobtained melting at 204° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.60 (2H, s, NCH₂) 4.20 (2H, s, NCH₂),4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (7H, m, 7CH arom.), 7.55 (1H, d, J=7 Hz, CH arom.)].

[0341]1-Benzhydryl-3-[(2-chlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(2-chlorobenzyl)methylsulfone and 4.6 g of 1-benzhydrylazetidin-3-one,the residue obtained is taken up in 50 cm³ of ethyl acetate, filteredand dried. 2.4 g of1-benzhydryl-3-[(2-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0342] (2-Chlorobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.4 g of (2-chlorobenzyl)methylsulfide and 12 gof oxone^(R), 4 g of (2-chlorobenzyl)methylsulfone are obtained in theform of an oil which crystallizes. (2-Chlorobenzyl)methylsulfide may beprepared in the following manner: on carrying out the operationaccording to the procedure of Example 2 but starting with 4 g of2-chlorobenzyl bromide and 1.5 g of sodium methylthiolate, 3.4 g of(2-chlorobenzyl)methylsulfide are obtained in the form of an oil.

EXAMPLE 6

[0343] On carrying out the operation according to the procedure ofExample 4 starting with 3 g of1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.79 cm³ of methanesulfonyl chloride and 3.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 2to 5 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 40 cm³ of ethylether. 1.7 g of1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 205° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (8H, m, 8CH arom.)].l-benzhydryl-3-[(3-chlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.1 g of(3-chlorobenzyl)methylsulfone and 3.4 g of 1-benzhydrylazetidin-3-one,3.4 g of1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0344] (3-Chlorobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.2 g of (3-chlorobenzyl)methylsulfide and 12 gof oxone^(R), 3.2 g of (3-chlorobenzyl)methylsulfone are obtained in theform of a white solid.

[0345] (3-Chlorobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4 g of 3-chlorobenzyl bromide and 1.5 g ofsodium methylthiolate, 3.2 g of 3-chlorobenzylmethylsulfide are obtainedin the form of an oil.

EXAMPLE 7

[0346] On carrying out the operation according to the procedure ofExample 4 starting with 3.3 g of1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.87 cm³ of methanesulfonyl chloride and 3.6 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 8to 12 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 3 cm³and 30 cm³ of ethyl ether. 0.5 g of1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)-methylene]azetidine isobtained melting at 192° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), between 7.40 and 7.55 (8H, m, 8CH arom.)].

[0347]1-Benzhydryl-3-[(4-chlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.8 g of(4-chlorobenzyl)methylsulfone and 3.24 g of 1-benzhydrylazetidin-3-one,3.4 g of1-benzhydryl-3-[(4-chlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid after crystallization from 80cm³.

[0348] (4-Chlorobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.5 g of (4-chlorobenzyl)methylsulfide and 12.3g of oxone^(R), 3.5 g of (4-chlorobenzyl)methylsulfone are obtained inthe form of a solid.

EXAMPLE 8

[0349] On carrying out the operation according to the procedure ofExample 4 starting with 3.1 g of1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,0.75 cm³ of methanesulfonyl chloride and 3.1 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 6to 10 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 2 cm³ ofdichloromethane and 30 cm³ of ethyl ether. 0.8 g of1-benzhydryl-3-[(3,5-dichlorophenyl)-(methylsulfonyl)methylene]azetidineis obtained melting at 204° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 2.95 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (1H, s, CH arom.)].

[0350]1-Benzhydryl-3-[(3,5-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(3,5-dichlorobenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one,3.2 g of1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0351] (3,5-Dichlorobenzyl)methylsulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 5.3 g of(3,5-dichlorobenzyl)-methylsulfide and 17 g of oxone^(R), 5 g of(3,5-dichlorobenzyl)methylsulfone are obtained in the form of a whitesolid.

[0352] (3,5-Dichlorobenzyl)methylsulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 5 g of 3,5-dichlorobenzyl chlorideand 2 g of sodium methylthiolate, 5.3 g of(3,5-dichlorobenzyl)methylsulfide are obtained in the form of an oil.

EXAMPLE 9

[0353] On carrying out the operation according to the procedure ofExample 4 starting with 5 g of1-benzhydryl-3-[(3,4-dichlorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,1.2 cm³ of methanesulfonyl chloride and 3.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with amixture of cyclohexane and ethyl acetate (70/30 by volume) as eluent andcollecting 35 cm³ fractions. Fractions 30 to 55 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 50 cm³ of ethyl ether. 1.5 g of1-benzhydryl-3-[(3,4-dichlorophenyl)-(methylsulfonyl)methylene]azetidineare obtained melting at 170° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), between 7.35 and 7.50 (5H, m, 5CH arom.), 7.65 (2H,m, 2CH arom.)].

[0354]1-Benzhydryl-3-[(3,4-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4.5 g of(3,4-dichlorobenzyl)-methylsulfone and 4.3 g of1-benzhydrylazetidin-3-one, 5 g of1-benzhydryl-3-[(3,4-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0355] (3,4-Dichlorobenzyl)methylsulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 4.3 g of(3,4-dichlorobenzyl)-methylsulfide and 13 g of oxone^(R), 4.7 g of(3,4-dichlorobenzyl)methylsulfone are obtained in the form of a whitesolid.

[0356] (3,4-Dichlorobenzyl)methylsulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 2.8 cm³ of 3,4-dichlorobenzylchloride and 1.5 g of sodium methylthiolate, 4.3 g of(3,4-dichlorobenzyl)methylsulfide are obtained in the form of an oil.

EXAMPLE 10

[0357] On carrying out the operation according to the procedure ofExample 4 starting with 1.8 g of1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,0.4 cm³ of methanesulfonyl chloride and 1.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 8to 14 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from a mixture of 2 cm³ ofdichloromethane and 30 cm³ of ethyl ether. 1.2 g of1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 202° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.70 (2H, m, NCH₂) 4.25 (2H, m,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), between 7.55 and7.70 (3H, m, 3CH arom.)].

[0358]1-Benzhydryl-3-[(2,5-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 1.2 g of(2,5-dichlorobenzyl)-methylsulfone and 1.2 g of1-benzhydrylazetidin-3-one, 1.8 g of1-benzhydryl-3-[(2,5-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0359] (2,5-Dichlorobenzyl)methylsulfone may be prepared in thefollowing manner: 1.9 g of sodium methanesulfinate are added, at roomtemperature, to a solution of 2.7 g of 2,5-dichlorobenzyl chloride in 30cm³ of ethanol. The mixture is heated under reflux for 5 hours, cooledto room temperature and then taken up in 50 cm³ of water and 50 cm³ ofethyl acetate. The organic phase is decanted off, washed with 20 cm³ ofa saturated aqueous sodium chloride solution, dried over magnesiumsulfate and concentrated to dryness under reduced pressure (2.7 kPa).1.2 g of (2,5-dichlorobenzyl)methylsulfone are obtained in the form of awhite solid.

EXAMPLE 11

[0360] On carrying out the operation according to the procedure ofExample 4 starting with 9.1 g of1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,2.2 cm³ of methanesulfonyl chloride and 7 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 40 cm³ fractions. Fractions 27 to 39 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 20 cm³ of ethyl ether. 1.5 g of1-benzhydryl-3-[(2,4-dichlorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 165° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.65 (2H, m, NCH₂), 4.25 (2H, m,NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.80 (1H, s, CH arom.)].

[0361]1-Benzhydryl-3-[(2,4-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4.8 g of(2,4-dichlorobenzyl)-methylsulfone and 4.7 g of1-benzhydrylazetidin-3-one, 9.1 g of1-benzhydryl-3-[(2,4-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a brown foam.

[0362] (2,4-Dichlorobenzyl)methylsulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 4 g of(2,4-dichlorobenzyl)methylsulfide and 13 g of oxone^(R), 4.8 g of(2,4-dichlorobenzyl)-methylsulfone are obtained in the form of a whitesolid melting at 111° C.

[0363] (2,4-Dichlorobenzyl)methylsulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 2.8 cm³ of 2,4-dichlorobenzylchloride and 1.5 g of sodium methylthiolate, 4 g of(2,4-dichlorobenzyl)methylsulfide are obtained in the form of an oil.

EXAMPLE 12

[0364] On carrying out the operation according to the procedure ofExample 4 starting with 3 g of1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,1.1 g of methanesulfonyl chloride and 3 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at anitrogen pressure of 0.5 bar with a mixture of dichloromethane andethanol (98/2 by volume) as eluent and collecting 100 cm³ fractions.Fractions 10 to 20 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from 40cm³ of ethyl ether. 1.6 g of1-benzhydryl-3-[(2,3-dichlorophenyl)-(methylsulfonyl)methylene]azetidineare obtained melting at 201° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.60 (2H, m, NCH₂), 4.20 (2H, m,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (6H, m, 6CH arom.), 7.70 (1H, dd, J=8 and 2 Hz,CH arom.)].

[0365]1-Benzhydryl-3-[(2,3-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.6 g of(2,3-dichlorobenzyl).-methylsulfone and 3.6 g of1-benzhydrylazetidin-3-one, 5.4 g of1-benzhydryl-3-[(2,3-dichlorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0366] (2,3-Dichlorobenzyl)methylsulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 10 starting with 3 g of 2,3-dichlorobenzyl chlorideand 2.4 g of sodium methanesulfinate, 3.6 g of(2,3-dichlorobenzyl)methylsulfonate are obtained in the form of a whitesolid.

EXAMPLE 13

[0367] On carrying out the operation according to the procedure ofExample 4 starting with 2.5 g of1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.72 cm³ of methanesulfonyl chloride and 2.9 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent, collecting 100 cm³ fractions. Fractions 2 to6 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from 40 cm³ of ethyl ether. 1.5g of1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)-methylene]azetidine areobtained melting at 210° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, m, NCH₂), 4.20 (2H, s, NCH₂),4.70 (1H, s, NCH), between 7.10 and 7.30 (9H, m, 9CH arom.), 7.45 (5H,m, 5CH arom.)].

[0368]1-Benzhydryl-3-[(3-fluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.6 g of3-fluorobenzyl methyl sulfone and 3.3 g of 1-benzhydrylazetidin-3-one,2.9 g of1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid melting at 200° C.

[0369] (3-Fluorobenzyl) methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.1 g of 3-fluorobenzyl methyl sulfide and 13 gof oxone^(R), 2.7 g of 3-fluorobenzyl methyl sulfone are obtained in theform of a white solid.

[0370] (3-Fluorobenzyl) methyl sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 2.6 cm³ of 3-fluorobenzyl bromide and 1.6 g ofsodium methylthiolate, 3.1 g of 3-fluorobenzyl-methyl sulfide areobtained in the form of an oil.

EXAMPLE 14

[0371] On carrying out the operation according to the procedure ofExample 4 starting with 4.3 g of1-benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.2 cm³ of methanesulfonyl chloride and 3.7 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4.5 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 30 cm³ fractions. Fractions 28to 58 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 100 cm³ of ethylether. 2.3 g of1-benzhydryl-3-[(2-fluorophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 188° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.65 (2H, m, NCH₂)₁ 4.20 (2H, m, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (6H, m, 6CHarom.), 7.50 (6H, m, 6CH arom.)].

[0372]1-Benzhydryl-3-[(2-fluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.4 g of2-fluorobenzyl methyl sulfone and 4.2 g of 1-benzhydrylazetidin-3-one,4.3 g of1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0373] (2-Fluorobenzyl) methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3 g of 2-fluorobenzyl methyl sulfide and 13 g ofoxone^(R), 3.6 g of 3-fluorobenzyl methyl sulfone are obtained in theform of a white solid.

[0374] (2-Fluorobenzyl) methyl sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 2.4 cm³ of 2-fluorobenzyl bromide and 1.5 g ofsodium methylthiolate, 3 g of 2-fluorobenzyl methyl sulfide are obtainedin the form of an oil.

EXAMPLE 15

[0375] On carrying out the operation according to the procedure ofExample 4 starting with 1 g of1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 0.9 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 30 cm³ fractions. Fractions 20to 35 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 50 cm³ of ethylether. 0.4 g of1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 186° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, m, NCH₂), 4.20 (2H, m, NCH₂),4.75 (1H, s, NCH), between 7.15 and 7.35 (8H, m, 8CH arom.), 7.45 (6H,m, 6CH arom.)].

[0376]1-Benzhydryl-3-[(4-fluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.8 g of4-fluorobenzyl methyl sulfone and 3.6 g of 1-benzhydrylazetidin-3-one, 1g of1-benzhydryl-3-[(4-fluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained in the form of a white solid.

[0377] (4-Fluorobenzyl) methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3 g of 4-fluorobenzyl methyl sulfide and 13 g ofoxone^(R), 3 g of 4-fluorobenzyl methyl sulfone are obtained in the formof a white solid melting at 110° C.

[0378] (4-Fluorobenzyl) methyl sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 2.5 cm³ of 4-fluorobenzyl chloride and 1.5 g ofsodium methylthiolate, 3 g of 4-fluorobenzyl methyl sulfide are obtainedin the form of an oil.

EXAMPLE 16

[0379] On carrying out the operation according to the procedure ofExample 4 starting with 3.8 g of1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,1 cm³ of methanesulfonyl chloride and 4.2 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting100 cm³ fractions. Fractions 5 to 10 are combined and concentrated todryness under reduced pressure (2.7 kPa). The solid obtained iscrystallized from 30 cm³ of ethyl ether. 0.8 g of1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 172° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, m, NCH₂), 4.20 (2H, m,NCH₂), 4.75 (1H, s, NCH), between 7.10 and 7.40 (9H, m, 9CH arom.), 7.50(4H, d, J=7 Hz, 4CH arom.)].

[0380]1-Benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.2 g of3,5-difluorobenzyl methyl sulfone and 3.7 g of1-benzhydrylazetidin-3-one, 3.9 g of1-benzhydryl-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0381] (3,5-Difluorobenzyl) methyl sulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 4.2 g of 3,5-difluorobenzyl methylsulfide and 16 g of oxone^(R), 3.3 g of 3,5-difluorobenzyl methylsulfone are obtained in the form of a white solid.

[0382] (3,5-Difluorobenzyl) methyl sulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 5 g of 3,5-difluorobenzyl bromideand 2 g of sodium methylthiolate, 4.9 g of 3,5-difluorobenzyl methylsulfide are obtained in the form of an oil.

EXAMPLE 17

[0383] On carrying out the operation according to the procedure ofExample 4 starting with 5.2 g of1-benzhydryl-3-[(2,3-difluorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,2.3 cm³ of methanesulfonyl chloride and 7.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and methanol (98/2 by volume) as eluent andcollecting 50 cm³ fractions. Fractions 65 to 87 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 75 cm³ of ethyl ether. 2.5 g of1-benzhydryl-3-[(2,3-difluorophenyl)-(methylsulfonyl)methylene]azetidineare obtained melting at 208° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (400 MHz): 3.05 (3H, s, SCH₃), 3.70 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.55 (13H, m, 13CH arom.)].

[0384]1-Benzhydryl-3-[(2,3-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(2,3-difluorobenzyl) methyl sulfone and 4.8 g of1-benzhydrylazetidin-3-one, 5.5 g of1-benzhydryl-3-[(2,3-difluorophenyl)(methyl-sulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a beige solid.

[0385] (2,3-Difluorobenzyl) methyl sulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 10 starting with 4.1 g of 2,3-difluorobenzylbromide and 4.1 g of sodium methanesulfinate, 4 g of(2,3-difluoro-benzyl) methyl sulfone are obtained in the form of a whitesolid.

EXAMPLE 18

[0386] On carrying out the operation according to the procedure ofExample 4 starting with 5.2 g of1-benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,2.3 cm³ of methanesulfonyl chloride and 7.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and methanol (98/2 by volume) as eluent andcollecting 50 cm³ fractions. Fractions 73 to 90 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 75 cm³ of ethyl ether. 2.6 g of1-benzhydryl-3-[(2,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 176° C.

[0387]1-Benzhydryl-3-[(2,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(2,5-difluorobenzyl) methyl sulfone and 4.8 g of1-benzhydrylazetidin-3-one, 5.9 g of1-benzhydryl-3-[(2,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a cream-colored solid.

[0388] (2,5-Difluorobenzyl) methyl sulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 10 starting with 4.1 g of 2,5-difluorobenzylbromide and 4.1 g of sodium methanesulfinate, 4.8 g of(2,5-difluorobenzyl) methyl sulfone are obtained in the form of a whitesolid melting at 95° C.

EXAMPLE 19

[0389] On carrying out the operation according to the procedure ofExample 4 starting with 7.7 g of1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.8 cm³ of methanesulfonyl chloride and 5.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a dichloromethane and ethanol mixture (99.5/0.5by volume) as eluents and collecting 100 cm³ fractions. Fractions 17 to28 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from a mixture of 5 cm³ ofdichloromethane and 50 cm³ of ethyl ether. 3.5 g of1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 200° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂) 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), between 7.35 and 7.55 (6H, m, 6CH arom.), 7.65 (2H, m, 2CHarom.)].

[0390]1-Benzhydryl-3-[(3-bromophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 8 g of3-bromobenzyl methyl sulfone and 7.6 g of 1-benzhydrylazetidin-3-one, 8g of1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0391] 3-Bromobenzyl methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 9 g of 3-bromobenzyl methyl sulfide and 27 g ofoxone^(R), 8.2 g of 3-bromobenzyl methyl sulfone are obtained in theform of a white solid.

[0392] 3-Bromobenzyl methyl sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 10 g of 3-bromobenzyl bromide and 3.1 g ofsodium methylthiolate, 9 g of 3-bromobenzyl methyl sulfide are obtainedin the form of an oil.

EXAMPLE 20

[0393] On carrying out the operation according to the procedure ofExample 4 starting with 1.5 g of1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 1.4 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a mixture of dichloromethane and ethanol(99.7/0.3 by volume) as eluents and collecting 100 cm³ fractions.Fractions 16 to 24 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from amixture of 1.5 cm³ of dichloromethane and 25 cm³ of ethyl ether. 0.5 gof 1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 198° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), between 7.10 and 7.30 (7H, m, 7CH arom.), 7.45 (5H,m, 5CH arom.), 7.80 (2H, m, 2CH arom.)].

[0394]1-Benzhydryl-3-[(3-iodophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.7 g of3-iodobenzyl methyl sulfone and 3 g of 1-benzhydrylazetidin-3-one, 1.5 gof1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0395] 3-Iodobenzyl methyl sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.6 g of 3-iodobenzyl methyl sulfide and 10.3 gof oxone^(R), 3.7 g of 3-iodobenzyl methyl sulfone are obtained in theform of a white solid.

[0396] 3-Iodobenzyl methyl sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5 g of 3-iodobenzyl bromide and 1.3 g of sodiummethylthiolate, 4 g of 3-iodobenzyl methyl sulfide are obtained in theform of an oil.

EXAMPLE 21

[0397] On carrying out the operation according to the procedure ofExample 4 starting with 2.4 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-ol,0.6 cm³ of methanesulfonyl chloride and 2.3 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a mixture of dichloromethane and ethanol(99.7/0.3 by volume) as eluents and collecting 100 cm³ fractions.Fractions 12 to 25 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from amixture of 2 cm³ of dichloromethane and 30 cm³ of ethyl ether. 0.7 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methylene]azetidineis obtained melting at 162° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.40 (6H, m, 6CH arom.),between 7.45 and 7.55 (7H, m, 7CH arom.), 7.60 (1H, t, J=7 Hz, CHarom.)].

[0398]1-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2.4 g ofmethyl(3-trifluoromethoxybenzyl)sulfone and 2.2 g of1-benzhydrylazetidin-3-one, 2.4 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxyphenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0399] Methyl(3-fluoromethoxybenzyl)sulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 2.6 g ofmethyl(3-trifluoromethoxybenzyl)sulfide and 7.2 g of oxone^(R), 2.4 g ofmethyl-(3-trifluoromethoxybenzyl)sulfone are obtained in the form of awhite solid.

[0400] Methyl(3-trifluoromethoxybenzyl)sulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 3 g of 3-trifluoromethoxybenzylbromide and 1 g of sodium methylthiolate, 3.3 g ofmethyl-(3-trifluoromethoxybenzyl)sulfide are obtained in the form of anoil.

EXAMPLE 22

[0401] On carrying out the operation according to the procedure ofExample 4 starting with 4.1 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS)]azetidin-3-ol,1 cm³ of methanesulfonyl chloride and 4.2 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3 cm, height 35 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent, collecting100 cm³ fractions. Fractions 10 to 14 are combined and concentrated todryness under reduced pressure (2.7 kPa). The solid obtained iscrystallized from a mixture of 2 cm³ of dichloromethane and 30 cm³ ofethyl ether. 1.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methylene]-azetidineare obtained melting at 178° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.15 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), between 7.60 and7.80 (4H, m, 4CH arom.)].1-Benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.4 g ofmethyl(3-trifluoromethylbenzyl)sulfone and 3.4 g of1-benzhydrylazetidin-3-one, 4.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylphenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0402] Methyl(3-trifluoromethylbenzyl)sulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 3.3 g ofmethyl(3-trifluoromethylbenzyl)sulfide and 10 g of oxone^(R), 3.4 g ofmethyl(3-trifluoromethylbenzyl)sulfone are obtained in the form of awhite solid.

[0403] Methyl(3-trifluoromethylbenzyl)sulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 3.9 g of 3-trifluoromethylbenzylbromide and 1.4 g of sodium methylthiolate, 3.3 g ofmethyl-(3-trifluoromethylbenzyl)sulfide are obtained in the form of anoil.

EXAMPLE 23

[0404] On carrying out the operation according to the procedure ofExample 4 starting with 2.7 g of1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl]-(methylsulfonyl)methyl-(RS)}azetidin-3-ol,0.6 cm³ of methanesulfonyl chloride and 2.4 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6 cm, height 40 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent, collecting 100 cm³ fractions. Fractions 7 to12 are combined and concentrated to dryness under reduced pressure (2.7kPa). The solid obtained is crystallized from 10 cm³ of ethyl ether. 1 gof1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidineis obtained melting at 192° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.15 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.15 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 8.05 (2H, s, 2CHarom.), 8.15 (1H, s, CH arom.)].

[0405]1-Benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methylene}azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.1 g ofmethyl[3,5-bis(trifluoromethyl)-benzyl]sulfone and 2.4 g of1-benzhydrylazetidin-3-one, 2.8 g of1-benzhydryl-3-{[(3,5-bis(trifluoromethyl)-phenyl](methylsulfonyl)methylene}azetidin-3-olare obtained in the form of a white solid.

[0406] Methyl[3,5-bis(trifluoromethyl)benzylsulfone may be prepared inthe following manner: on carrying out the operation according to theprocedure of Example 10 starting with 3 g of3,5-bis(trifluoromethyl)benzyl chloride and 2 g of sodiummethanesulfinate, 3.1 g of methyl[3,5-bis(trifluoromethyl)benzyl]sulfoneare obtained in the form of a white solid melting at 132° C.

EXAMPLE 24

[0407] On carrying out the operation according to the procedure ofExample 4 starting with 10.7 g of1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,2.2 cm³ of methanesulfonyl chloride and 7 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 35 cm³ fractions. Fractions 40 to 58 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 50 cm³ of ethyl ether. 1.5 g of1-benzhydryl-3-[3,5-dibromophenyl)(methylsulfonyl)methylene]azetidineare obtained melting at 209° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (250 MHz): 3.00 (3H, s, SCH₃), 3.88 (2H, s, NCH₂), 4.22 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.33 (4H, t,J=7 Hz, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 7.68 (2H, s, 2CHarom.), 7.95 (1H, s, CH arom.)].1-Benzhydryl-3-[(3,5-dibromophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 6.2 g of(3,5-dibromobenzyl)methylsulfone and 4.5 g of1-benzhydrylazetidin-3-one, 10.7 g of1-benzhydryl-3-[3,5-dibromophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

[0408] (3,5-Dibromobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5.8 g of (3,5-dibromobenzyl)methylsulfide and 13g of oxone^(R), 6.2 g of (3,5-dibromobenzyl)methylsulfone are obtainedin the form of a white solid.

[0409] (3,5-Dibromobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 6.6 g of 3,5-dibromobenzyl bromide and 1.5 g ofsodium methylthiolate, 5.8 g of (3,5-dibromobenzyl)methylsulfide areobtained in the form of an oil.

EXAMPLE 25

[0410] On carrying out the operation according to the procedure ofExample 4 starting with 4.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl-(RS)]azetidin-3-ol,1.1 cm³ of methanesulfonyl chloride and 2.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 35 cm) at a nitrogen pressure of 0.5 bar with amixture of cyclohexane and ethyl acetate (50/50 by volume) as eluents,collecting 400 cm³ fractions. Fractions 17 to 33 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is recrystallized from 15 cm³ of ethyl acetate. 0.6 g of1-benzhydryl-3-[(methylsulfonyl)-(3-nitrophenyl)methylene]azetidine isobtained melting at 184° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.25 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.75 (1H, t, J=7 Hz, CHarom.), 7.85 (1H, d, J=7 Hz, CH arom.), 8.25 (2H, m, 2CH arom.)].

[0411]1-Benzhydryl-3-[(methylsulfonyl)-(3-nitrophenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.9 g ofmethyl(3-nitrobenzyl)sulfone and 4.2 g of 1-benzhydrylazetidin-3-one,4.2 g of1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

[0412] Methyl(3-nitrobenzyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 but starting with 18.1 g of methyl(3-nitrobenzyl)sulfide and68 g of oxone^(R), 13.9 g of methyl(3-nitrobenzyl)sulfone are obtainedin the form of a foam.

[0413] Methyl(3-nitrobenzyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 17.2 g of 3-nitrobenzyl chloride and 7.7 g ofsodium methylthiolate, 18.2 g of methyl (3-nitrobenzyl) sulfide areobtained in the form of an oil.

EXAMPLE 26

[0414] A mixture of 0.34 g of1-benzhydryl-3-[(methylsulfonyl)(3-nitrophenyl)methylene]azetidine, 16cm³ of 1 N hydrochloric acid in 8 cm³ of ethanol and 16 cm³ oftetrahydrofuran is heated under reflux. 0.17 g of iron powder is addedand the reflux is maintained for 3 hours. The mixture is then cooled toroom temperature and the insoluble matter is filtered off. The solutionis taken up in 10 cm³ of 1 N sodium hydroxide and 50 cm³ of a saturatedaqueous sodium chloride solution. The aqueous phase is extracted with 3times 40 cm³ of dichloromethane, the extracts are combined, dried oversodium sulfate and concentrated to dryness under reduced pressure (2.7kPa). The residue is purified on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5bar with a mixture of cyclohexane and ethyl acetate (50/50 by volume) aseluent, collecting 20 cm³ fractions. Fractions 13 to 31 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 15 Cm³ of ethyl ether. 0.17 g of3-[(3-aminophenyl)-(methylsulfonyl)methylene]-1-benzhydrylazetidine isobtained melting at 197° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(250 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 5.25 (2H, s, NH₂), 6.55 (3H, m, 3CH arom.), 7.05 (1H,t, J=7 Hz, CH arom.), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].

EXAMPLE 27

[0415] On carrying out the operation according to the procedure ofExample 4 starting with 1.2 g of1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 1.3 g of4-dimethylamino-pyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a mixture of dichloromethane and ethyl acetate(99.5/0.5 by volume) as eluents and collecting 100 cm³ fractions.Fraction 18 is concentrated to dryness under reduced pressure (2.7 kPa).The solid obtained is precipitated in 5 cm³ of ethyl ether. 0.13 g of1-benzhydryl-3-[(3-methoxycarbonylphenyl)-(methylsulfonyl)methylene]azetidineis obtained in the form of a foamy solid [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30(4H, t, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.60 (1H,t, J=7 Hz, CH arom.), 7.70 (1H, d, J=7 Hz, CH arom.), 8.00 (2H, m, 2CHarom.)].

[0416]1-Benzhydryl-3-[(3-methoxycarbonylphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3 g of(3-methoxycarbonylbenzyl)-methylsulfone and 3.6 g of1-benzhydrylazetidin-3-one, 1.2 g of1-benzhydryl-3-[(3-methoxycarbonylphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam after purification by chromatographyon a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm,height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane andthen a dichloromethane and ethanol mixture (99/1 by volume) as eluents.

[0417] (3-Methoxycarbonylbenzyl)methylsulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 4.3 g of(3-methoxycarbonylbenzyl)methylsulfide and 13.4 g of oxone^(R), 3.4 g of(3-methoxycarbonylbenzyl)methylsulfone are obtained in the form of awhite solid.

[0418] (3-Methoxycarbonylbenzyl)methylsulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 5 g of 3-methoxycarbonylbenzylbromide and 1.7 g of sodium methylthiolate, 4.3 g of(3-methoxycarbonylbenzyl)methylsulfide are obtained in the form of anoil.

EXAMPLE 28

[0419] On carrying out the operation according to the procedure ofExample 4 starting with 6.2 g of1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.6 cm³ of methanesulfonyl chloride and 6.8 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane and then a dichloromethane and ethyl acetate mixture(99.5/0.5 by volume) as eluents and collecting 250 cm³ fractions.Fractions 10 to 15 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from amixture of 5 cm³ of dichloromethane and 70 cm³ of ethyl ether. 2.9 g of1-benzhydryl-3-[(3-cyanophenyl)-(methylsulfonyl)methylene]azetidine areobtained melting at 152° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz,4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.65 (1H, t, J=7 Hz, CHarom.), 7.75 (1H, d, J=7 Hz, CH arom.), 7.90 (2H, m, 2CH arom.)].

[0420]1-Benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.9 g of(3-cyanobenzyl)methylsulfone and 4.7 g of 1-benzhydrylazetidin-3-one,6.2 g of1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0421] (3-Cyanobenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 6.7 g of (3-cyanobenzyl)methylsulfide and 27.6 gof oxone^(R), 3.9 g of (3-cyanobenzyl)methylsulfone are obtained in theform of a white solid.

[0422] (3-Cyanobenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 8 g of 3-cyanobenzyl bromide and 3.1 g of sodiummethylthiolate, 6.8 g of (3-cyanobenzyl)methylsulfide are obtained inthe form of an oil.

EXAMPLE 29

[0423] A mixture of 3 g of1-benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride, 1.3 g of pentafluorophenol, 1.4 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 30 cm³ ofdimethylformamide is stirred at room temperature for 15 hours. Themixture is taken up in 100 cm³ of water and 100 cm³ of a saturatedaqueous sodium chloride solution and 50 cm³ of ethyl acetate. Theorganic phase is decanted off, dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). The residue ispurified by chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 35 cm) at a nitrogen pressure of 0.5bar with dichloromethane and then a dichloromethane and methanol mixture(99.4/0.6 by volume) as eluents and collecting 100 cm³ fractions.Fractions 13 to 16 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from 10cm³ of ethyl ether. 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(3-pentafluorophenoxycarbonylphenyl)methylene]azetidineis obtained melting at 182° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (400 MHz): 3.00 (3H, s, SCH₃), 3.85 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.70 (1H, t, J=7Hz, CH arom.), 8.20 (2H, m, 2CH arom.)].

[0424]1-Benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride may be prepared in the following manner: a mixture of 10 gof 1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine in40 cm³ of acetic acid and 40 cm³ of concentrated hydrochloric acid(d=1.18) is heated at 45° C. for 7 days. The reaction medium is cooledon an ice-cold water bath and the precipitate formed is filtered onsintered glass. The solid is washed with 20 cm³ of a mixture of aceticacid and concentrated hydrochloric acid (50-50 by volume) and then with3 times 20 cm³ of water and finally with 20 cm³ of ethanol. The whitesolid obtained is under reduced pressure (2.7 kPa) at 45° C. and 2.5 gof 1-benzhydryl-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride are obtained in the form of a white solid.

EXAMPLE 30

[0425] A solution of 0.65 g of1-benzhydryl-3-[(methylsulfonyl)(3-pentafluorophenoxycarbonylphenyl)methylene]azetidine in 25 cm³ of 6.2 N ammoniacal ethanol is stirred for4 hours at room temperature. The mixture is concentrated to drynessunder reduced pressure (2.7 kPa) and then the residue is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and ethanol mixture (99/1 by volume) and then adichloromethane and ethanol mixture (98/2 by volume) as eluents andcollecting 60 cm³ fractions. Fractions 18 to 30 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 0.2 g of1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]-azetidineis obtained melting at 140° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.25 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t,J=7 Hz, 4CH arom.), between 7.45 and 7.65 (7H, m, 6CH arom. and 2CONH₂), 7.95 (2H, m, 2CH arom.), 8.10 (1H, s, 2 CONH₂).

EXAMPLE 31

[0426] On carrying out the operation according to the procedure ofExample 4 starting with 4.6 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-ol,1.2 cm³ of methanesulfonyl chloride and 3.8 g of4-dimethylaminopyridine, 2.6 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine areobtained, after recrystallization from 150 cm³ of acetonitrile, meltingat 179° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm (250 MHz): 2.95(3H, s, SCH₃), 3.75 (3H, s, OCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.00 (3H, m, 3 CH arom.), between 7.20 and7.12 (11H, m, 10H phenyls and 1 CH arom.)].

[0427]1-Benzhydryl-3-[(3-methoxyphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.4 g of(3-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one,4.6 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid.

[0428] (3-Methoxybenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.4 g of (3-methoxybenzyl)methylsulfide and 13 gof oxone^(R), 4 g of (3-methoxybenzyl)methylsulfone are obtained in theform of a white solid melting at 710C.

[0429] (3-Methoxybenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.1 g of 3-methoxybenzyl bromide and 1.5 g ofsodium methylthiolate, 3.4 g of (3-methoxybenzyl)methylsulfide areobtained in the form of an oil.

EXAMPLE 32

[0430] 10 cm³ of a 1 M solution of boron tetrabromide in dichloromethaneare added, with stirring, to a solution of 1.3 g of1-benzhydryl-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine in100 cm³ of dichloromethane. The stirring is maintained for 16 hours atroom temperature. The reaction medium is taken up in 100 cm³ of ice-coldwater. The organic phase is washed with 3 times 50 cm³ of water, driedover magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). The residue is precipitated in 150 cm³ of isopropylether and then dissolved in 50 cm³ of dichloromethane. The organic phaseis washed with 3 times 30 cm³ of a saturated aqueous solution of sodiumbicarbonate, decanted off, dried over magnesium sulfate and concentratedto dryness under reduced pressure (2.7 kPa). The residue is precipitatedin 80 cm³ of ethyl ether. 0.36 g of1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine isobtained from a solid melting at 248° C. [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.75 (1H, s, NCH), 6.85 (3H, m, 3 CH arom.), 7.25 (3H, m,3 CH arom.), 7.35 (4H, t, J=7 Hz, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CHarom.), 9.50 (1H, s, OH)].

EXAMPLE 33

[0431] On carrying out the operation according to the procedure ofExample 32 starting with 1.4 g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine, 10cm³ of a 1 M boron tribromide solution and 100 cm³ of dichloromethane,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 3.5 cm, height 24 cm) at anitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethylacetate (50/50 by volume) as eluents and collecting 25 cm³ fractions.Fractions 21 to 37 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from amixture of 30 cm³ of ethyl ether. 0.6 g of1-benzhydryl-3-[(4-hydroxyphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 211° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.90 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 6.80 (2H, d, J=7 Hz, 2CH arom.), between 7.10 and7.35 (8H, m, 8CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 9.80 (1H, s,OH)].

[0432]1-Benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine maybe obtained in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 3.5 g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.9 cm³ of methanesulfonyl chloride and 2.9 g of4-dimethylaminopyridine, the residue obtained is purified byrecrystallization from 100 cm³ of acetonitrile. 1 g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 181° C.

[0433]1-Benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.5 g of(4-methoxybenzyl)methylsulfone and 4 g of 1-benzhydrylazetidin-3-one,3.6 g of1-benzhydryl-3-[(4-methoxyphenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olare obtained in the form of a white solid.

[0434] (4-Methoxybenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.4 g of (4-methoxybenzyl)methylsulfide and 13 gof oxone^(R), 3.5 g of (3-methoxybenzyl)methylsulfone are obtained inthe form of a white solid melting at 113° C.

[0435] (4-Methoxybenzyl)methylsulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 3.1 g of 4-methoxybenzyl chloride and 1.5 g ofsodium methylthiolate, 3.4 g of (4-methoxybenzyl)methylsulfide areobtained in the form of an oil.

EXAMPLE 34

[0436] On carrying out the operation according to the procedure ofExample 32 starting with 1.4 g of1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine, 10cm³ of a 1 M solution of boron tribromide and 100 cm³ ofdichloromethane, the residue obtained is purified by chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 30cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 40 cm³ fractions. Fractions 15 to 34 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 40 Cm³ of ethyl ether. 0.7 g of1-benzhydryl-3-[(2-hydroxyphenyl)(methylsulfonyl)methylene]azetidine isobtained melting at 196° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.60 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 6.85 (1H, t, J=7 Hz, CH arom.), 6.90 (1H, d, J=7 Hz,CH arom.), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.),7.48 (4H, d, J=7 Hz, 4CH arom.), 9.90 (1H, s, OH)].

[0437]1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine maybe obtained in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 4.2 g of1-benzhydryl-3-[(2-methoxyphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.1 cm³ of methanesulfonyl chloride and 3.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethyl acetate (50/50 by volume) aseluents and collecting 40 cm³ fractions. Fractions 23 to 54 are combinedand concentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 40 cm³ of ethyl ether. 1.9 g of1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine areobtained melting at 204° C.1-Benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4 g of(2-methoxybenzyl)methylsulfone and 4.5 g of 1-benzhydrylazetidin-3-one,4.3 g of1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olare obtained in the form of a brown foam.

[0438] (2-Methoxybenzyl)methylsulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 10 starting with 3.1 g of (2-methoxybenzyl) chloride and 4.1 gof sodium methanesulfinate, 4 g of (2-methoxybenzyl)methylsulfone areobtained in the form of a white solid.

EXAMPLE 35

[0439] On carrying out the operation according to the procedure ofExample 4 starting with 2.1 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]azetidin-3-ol,0.5 cm³ of methanesulfonyl chloride and 2.2 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 6to 10 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 20 cm³ of ethylether. 0.6 g of1-benzhydryl-3-[(methyl-sulfonyl)(naphth-2-yl)methylene]azetidine isobtained melting at 178° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.75 (1H, s, NCH), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7 Hz, 4CHarom.), 7.45 (4H, d, J=7 Hz, 4CH arom.), 7.52 (3H, m, 3CH arom.), 7.90(4H, m, 4CH arom.)].

[0440]1-Benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 3.5 g ofmethyl(naphth-2-ylmethyl)sulfone and 3.8 g of1-benzhydrylazetidin-3-one, 2.2 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-2-yl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid melting at 196° C.

[0441] Methyl(naphth-2-ylmethyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4.2 g of methyl(naphth-2-ylmethyl)sulfide and13.7 g of oxone^(R), 3.6 g of methyl(naphth-2-ylmethyl)sulfone areobtained in the form of a cream-colored solid.

[0442] Methyl(naphth-2-ylmethyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 5 g of (2-bromomethyl)naphthalene and 1.8 g ofsodium methylthiolate, 4.2 g of methyl(naphth-2-ylmethyl)sulfide areobtained in the form of an oil.

EXAMPLE 36

[0443] On carrying out the operation according to the procedure ofExample 4 starting with 4.3 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]azetidin-3-ol,1.1 cm³ of methanesulfonyl chloride and 4.6 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 6to 14 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 30 cm³ of ethylether. 2.5 g of 1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methylene]azetidine are obtained melting at 196° C. [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 3.00 (3H, s, SCH₃), 3.35 and 3.50 (1H each,dd, J=16 and 3 Hz, NCH₂), 4.35 (2H, m, NCH₂), 4.75 (1H, s, NCH), between7.10 and 7.70 (14H, m, 14CH arom.), 8.00 (3H, m, 3CH arom.)].

[0444]1-Benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 4.1 g ofmethyl(naphth-1-ylmethyl)sulfone and 4.4 g of1-benzhydrylazetidin-3-one, 4.3 g of1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)methyl-(RS)]azetidin-3-olare obtained in the form of a solid.

[0445] Methyl(naphth-1-ylmethyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4.3 g of methyl(naphth-1-ylmethyl)sulfide and13.9 g of oxone^(R), 4.1 g of methyl(naphth-1-yl-ethyl)sulfone areobtained in the form of a white solid.

[0446] Methyl(naphth-1-ylmethyl)sulfide may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 2 starting with 4 g of 1-chloromethylnaphthalene chloride and1.8 g of sodium methylthiolate, 4.5 g ofmethyl(naphth-1-ylmethyl)sulfide are obtained in the form of an oil.

EXAMPLE 37

[0447] On carrying out the operation according to the procedure ofExample 4 starting with 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(RS)]azetidin-3-ol,0.15 cm³ of methanesulfonyl chloride and 0.6 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and methanol mixture (98/2 by volume) as eluents andcollecting 20 cm³ fractions. Fractions 8 to 13 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 8 cm³ of ethyl ether. 0.36 g of1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methylene]azetidineis obtained melting at 153° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (250 MHz): 1.95 (4H, m, 2 CH₂), 2.95 (3H, s, SCH₃), 3.20 (4H, m, 2NCH₂), 3.80 (2H, S, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 6.60(3H, m, 3CH arom.), 7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7 Hz, 4CHarom.), 7.48 (4H, d, J=7 Hz, 4CH arom.)].1-Benzhydryl-3-[(methylsulfonyl)-(3-pyrrolidinophenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 0.77 g of3-pyrrolidinobenzyl methyl sulfone and 0.76 g of1-benzhydrylazetidin-3-one, 0.6 g of1-benzhydryl-3-[(methylsulfonyl)(3-pyrrolidinophenyl)methyl-(RS)]azetidin-3-olis obtained in the form of a solid.

[0448] Methyl(3-pyrrolidinobenzyl)sulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 1 g ofmethyl(3-pyrrolidinobenzyl)sulfide and 3.3 g of oxone^(R), 0.8 g ofmethyl(3-pyrrolidinobenzyl)sulfone is obtained in the form of a solid.

[0449] Methyl(3-pyrrolidinobenzyl)sulfide may be prepared in thefollowing manner: a mixture of 2 g of (3-iodobenzyl)methylsulfide, 1.3cm³ of pyrrolidine, 1.1 g of sodium tert-butoxide, 0.28 g of1,1′-bis(diphenylphosphino)ferrocenyl palladium chloride, 0.63 g of1,1′-bis(diphenylphosphino)ferrocene and 60 cm³ of tetrahydrofuran isheated under reflux, under a nitrogen stream, for 3 hours. The reactionmedium is cooled to room temperature and filtered on sintered glass. Theprecipitate is washed with 20 cm³ of tetrahydrofuran and 10 cm³ ofdichloromethane and then the filtrate is concentrated to dryness underreduced pressure (2.7 kPa). The residue is taken up with 30 cm³ of ethylacetate and 30 cm³ of 3 N hydrochloric acid. The aqueous phase isdecanted off, neutralized (pH=7-8) with 35 cm³ of 3 N sodium hydroxideand taken up in 50 cm³ of ethyl acetate. The organic phase is extracted;4 g of silica are added and then the mixture is concentrated to drynessunder reduced pressure (2.5 kPa). The powder obtained is eluted onsintered glass containing 20 g of silica with a mixture of cyclohexaneand ethyl acetate (90/10 by volume). The filtrate is concentrated todryness under reduced pressure (2.7 kPa). 1.2 g ofmethyl(3-pyrrolidinobenzyl)sulfide are obtained in the form of an oil.

[0450] 1,1′-Bis(diphenylphosphino)ferrocenyl palladium chloride may beprepared according to Hayashi T. et al., J. Am. Chem. Soc., 106, 158(1984).

EXAMPLE 38

[0451] Method 1

[0452]0.65 cm³ of methanesulfonyl chloride is added to a solution of2.94 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olin 250 cm³ of dichloromethane at 22° C., followed, in small portionsover 15 minutes, by 2.42 g of 4-dimethylaminopyridine; theorange-colored solution is stirred for 2 hours at room temperature. Thereaction mixture is washed 3 times with 150 cm³ of distilled water andonce with 150 cm³ of a saturated sodium chloride solution and then driedwith magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm, height15 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (1/9 by volume) as eluents and collecting 70 cm³fractions. Fractions 15 to 36 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 1.86 g of white foam areobtained, which foam is crystallized from isopropyl ether in order toobtain a solid melting at 190° C. A recrystallization from 145 cm³ ofethanol gives 1.08 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemelting at 206° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz):3.00 (3H, s, SCH₃), 3.87 (2H, s, NCH₁₂), 4.20 (2H, s, NCH₂), 4.75 (1H,s, NCH), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.), 7.45(4H, d, J=7 Hz, 4CH arom.)].

[0453] Method 2

[0454]0.80 g of ground sodium hydroxide is added to a solution of 2.2 gof3-acetoxy-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidinein 25 cm³ of dioxane at room temperature. After 16 hours at roomtemperature, 50 cm³ of water and 100 cm³ of ethyl acetate are added. Themixture is separated after settling out, the organic phase rewashed with100 cm³ of water, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). A white foamis obtained which is crystallized from isopropyl ether in order toobtain 0.85 g of a solid melting at 190° C. Recrystallization from 20cm³ of ethanol gives 0.70 g of1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemelting at 205° C.

EXAMPLE 39

[0455] 6.75 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and then 2.97 g of potassium carbonate are added to asolution of 6.8 g of bis(4-chlorophenyl)bromomethane in 300 cm³ ofacetonitrile. The reaction mixture is heated for 1 hour under reflux,cooled to room temperature, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 8.5 cm, height22 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (25/75 by volume) as eluents and collecting 250 cm³fractions. Fractions 11 to 48 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 5.3 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol are obtained. [¹H NMR spectrum (300 MHz,(CD₃)₂So-d6, δ in ppm): 2.00 (s, 3H), 2.94 (s, 3H), 3.25 (mt, 2H), 3.48(d, J=9 Hz, 1H), 3.80 (d, J=9 Hz, 1H), 4.54 (s, 1H), 5.34 (s, 1H), 7.15(d, J=8.5 Hz, 2H), from 7.20 to 7.40 (mt, 8H), 7.50 (broad t, J=9 Hz,1H)].

[0456] Bis(4-chlorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).

[0457] 3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride may be obtained in the following manner: 160 cm³ of a 6.2N hydrochloric acid solution in dioxane are added to a solution of 37 gof3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olin 160 cm³ of dioxane. After 16 hours at room temperature, the reactionmixture is concentrated to dryness under reduced pressure (2.7 kPa). Theresidue obtained is taken up in 320 cm³ of ethanol, heated for 1 hourunder reflux and cooled in an ice-cold water bath. The solid whichappears is filtered, washed with ethyl ether and dried at 40° C. underreduced pressure (2.7 kPa). 29.85 g of white crystals are obtained whosemelting point is greater than 260° C.

[0458]3-[(3,5-Difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olmay be obtained in the following manner: a solution of 14.0 cm³ of vinylchloroformate in 35 cm³ of dichloromethane is added at 5° C. to asolution of 60.18 g of1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olin 1000 cm³ of dichloromethane. After 20 hours at room temperature, thereaction mixture is concentrated to dryness under reduced pressure (2.7kPa). The residue obtained is chromatographed on a silica gel column(particle size 0.04-0.06 mm, diameter 11 cm, height 32 cm), at an argonpressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (3/7by volume) as eluents and collecting 1000 cm³ fractions. Fractions 8 to18 are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 37 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olare obtained in the form of white crystals melting at 195° C.

EXAMPLE 40

[0459] 14 cm³ of a 1.6 N n-butyllithium solution in hexane are added at−70° C. to a solution of 4.77 g of (3,5-difluorobenzyl)methylsulfone in70 cm³ of tetrahydrofuran under an argon atmosphere. After 1 hour at−70° C. , a solution of 6.8 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 30 cm³ of tetrahydrofuranis added and then, 1 hour later, a solution of 2.34 cm³ of acetylchloride in 20 Cm³ of tetrahydrofuran and the temperature of thereaction mixture is raised to 20° C. for 1 hour. 50 cm³ of water and 200cm³ of ethyl acetate are added. The mixture is separated after settlingout, the organic phase washed with 100 cm³ of water, 100 Cm³ of asaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (2.7 kPa).14.4 g of3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonyl-methyl-(RS)]azetidineare obtained in the form of a yellow oil [“H NMR spectrum (400 MHz,CDCl₃, δ in ppm): 2.79 (s, 3H), 3.04 (AB, J=9 Hz, 2H), 3.27 (d, J=9 Hz,1H), 3.45 (s, 1H), 3.81 (d, J=9 Hz, 1H), 4.32 (s, 1H), 4.49 (s, 1H),6.88 (tt, J=9 and 2.5 Hz, 1H), from 7.20 to 7.35 (mt, 10H)].

[0460] 1-[Bis(4-chlorophenyl)methyl]azetidin-3-one may be preparedaccording to the following procedure: a solution of 8.1 cm³ of dimethylsulfoxide in 17.6 cm³ of dichloromethane is added to a solution of 5.0cm³ of oxalyl chloride in 73 cm³ of dichloromethane cooled to −78° C.After 0.5 hour at −78° C. , a solution of 16.0 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-ol dissolved in 50 cm³ ofdichloromethane is poured in. After 5 hours at −78° C. , 26.6 cm³ oftriethylamine are added dropwise and the reaction mixture is allowed toreturn to room temperature. After 16 hours, the reaction mixture iswashed with 4 times 200 cm³ of water and then with 200 cm³ of asaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is chromatographed on a silica gel column (particlesize 0.04-0.06 mm, diameter 9.2 cm, height 21 cm) at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (40/60 byvolume) as eluents and collecting 200 cm³ fractions. Fractions 15 to 25are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 8.9 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one areobtained in the form of pale yellow crystals melting at 111° C.

[0461] 1-[Bis(4-chlorophenyl)methyl]azetidin-3-ol may be preparedaccording to the procedure described by KATRITZKY A. R. et al., J.Heterocycl. Chem., (1994), 271 starting with 35.5 g of[bis(4-chlorophenyl)methyl]amine hydrochloride and 11.0 cm³ ofepichlorohydrin. 9.0 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ol areisolated.

[0462] [Bis(4-chlorophenyl)methyl]amine hydrochloride may be preparedaccording to the method described by GRISAR M. et al., J. Med. Chem.,885 (1973).

EXAMPLE 41

[0463] On carrying out the operation according to the procedure ofExample 38 (Method 1), starting with 0.72 g of1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-oland after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 4.0 cm, height 16.5 cm) at an argon pressure of 0.5 barwith a mixture of ethyl acetate and cyclohexane (2/8 by volume) aseluent and collecting 40 cm³ fractions, 0.10 g of a white foam isobtained. After crystallization from a mixture of ethyl acetate andcyclohexane, 60 mg of1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a solid melting at 180° C. [NMR spectrum inDMSO-d6, T=300K, δ in ppm (250 MHz): 3.00 (3H, s, SCH₃), 3.70 (6H, s, 2OCH₃), 3.80 (2H, s, NCH₂), 4.15 (2H, s, NCH₂), 4.58 (1H, s, NCH), 6.85(4H, d, J=7 Hz, 4CH arom.), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (5H,m, 5CH arom.)].

[0464]1-[Bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to Example 39 starting with 1.2 g ofbis(4-methoxyphenyl)bromomethane and 1.2 g of3-[(3,5-difluorophenyl)(methylsulfonyl)-methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.8 cm, height 18 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 50 cm³ fractions, fractions 9 to 18 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.55 g of1-[bis(4-methoxyphenyl)-methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained.

[0465] Bis(4-methoxyphenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc. , 2135 (1933).

EXAMPLE 42

[0466] On carrying out the operation according to Example 38 (Method 1),starting with 0.47 g of1-[bis-(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-oland after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 3.2 cm, height 18.5 cm), at an argon pressure of 0.5 barwith a mixture of ethyl acetate and cyclohexane (1/9 by volume) aseluent and collecting 35 cm³ fractions, 0.30 g of a white solid isobtained. After crystallization from diisopropyl ether,

[0467] 0.20 g of1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of white needles melting at 200° C.1-[Bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationas in Example 39 starting with 0.7 g of bis(4-methylphenyl)bromomethaneand 0.8 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.0 cm, height 19 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (2/8 byvolume) as eluent and collecting 40 cm³ fractions, fractions 35 to 40are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.47 g of1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained.

[0468] Bis(4-methylphenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).

EXAMPLE 43

[0469] On carrying out the operation according to Example 38 (Method 1),starting with 1.42 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-ol,a mixture of the two diastereoisomers, and after chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 4.0 cm, height21 m), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (2/8 by volume) as eluent and collecting 40 cm³fractions, 0.10 g of a white solid is obtained. After crystallizationfrom diisopropyl ether, 50 mg of(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]-1-(4-methoxyphenyl)(phenyl)methyl]azetidineare obtained in the form of a white solid [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 2.23 (6H, s, 2 PhCH₃), 3.00 (3H, s, SCH₃),3.80 (2H, s, NCH₂), 4.12 (2H, s, NCH₂), 4.58 (1H, s, NCH), 7.08 (4H, d,J=7 Hz, 4CH arom.), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.25 (5H, m, 5CHarom.)]

[0470] The mixture of diastereoisomers3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to Example 39 starting with 2.52 g(RS)-bromo(4-methoxyphenyl)(phenyl)methane and 2.85 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 5.6 cm, height 19 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 100 cm³ fractions, fractions 11 to 18are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 1.16 g of the mixture of diastereoisomers3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-1-[(4-methoxyphenyl)(phenyl)methyl-(RS)]azetidin-3-olare obtained. (RS)-bromo(4-methoxyphenyl)(phenyl)methane may be preparedaccording to the procedure described by BACHMANN W. E., J. Am. Chem.Soc. , 2135 (1933).

EXAMPLE 44

[0471] On carrying out the operation as in Example 38 (Method 1),starting with 0.47 g of1-[bis-(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,and after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 4.2 cm, height 14 cm), at an argon pressure of 0.5 bar witha mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent andcollecting 25 cm³ fractions, 0.28 g of1-[bis-(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a solid [NMR spectrum in DMSO-d₆, T=300K, δin ppm (300 MHz): 3.05 (3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.25 (2H, s,NCH₂), 4.90 (1H, s, NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.32 (5H, m,5CH arom.), 7.60 (4H, d, J=7 Hz, 4CH arom.)].

[0472]1-[Bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationas in Example 39 starting with 1.59 g ofbis(4-trifluoromethoxyphenyl)bromomethane and 1.2 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 50 cm³ fractions, fractions 15 to 23are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.49 g of1-[bis-(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-olis obtained.

[0473] Bis(4-trifluoromethoxyphenyl)bromomethane may be preparedaccording to the procedure described by BACHMANN W. E., J. Am. Chem.Soc. , 2135 (1933), starting with 1.39 g ofbis(4-trifluoromethoxyphenyl)methanol, 3 cm³ of 33% hydrobromic acid inacetic acid and 0.6 cm³ of acetyl bromide. 1.59 g ofbis(4-trifluoromethoxyphenyl)bromomethane are obtained in the form of abrown oil.

[0474] Bis(4-trifluoromethoxyphenyl)methanol is prepared according toPAVIA M. R. et al., J. Med. Chem., 4238 (1992).

EXAMPLE 45

[0475] On carrying out the operation as in Example 38 (Method 1),starting with 0.25 g of1-[bis-(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,and after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 2.4 cm, height 14 cm), at an argon pressure of 0.5 bar witha mixture of ethyl acetate and cyclohexane (2/8 by volume) as eluent andcollecting 20 cm³ fractions, 0.12 g of1-[bis-(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 3.05 (3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.25(2H, s, NCH₂), 4.90 (1H, s, NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.32(5H, m, 5CH arom.), 7.60 (4H, d, J=7 Hz, 4CH arom.)].

[0476]1-[Bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationas in Example 39 starting with 1.46 g ofbis(4-trifluoromethylphenyl)bromomethane and 1.2 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.8 cm, height 17 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 byvolume) as eluent and collecting 50 cm³ fractions, fractions 9 to 14 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.25 g of1-[bis-(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained.

[0477] Bis(4-trifluoromethylphenyl)bromomethane may be preparedaccording to the procedure described by BACHMANN W. E., J. Am. Chem.Soc., 2135 (1933), starting with 2.5 g ofbis(4-trifluoromethylphenyl)methanol, 6 cm³ of 33% hydrobromic acid inacetic acid and 1.2 cm³ of acetyl bromide. 2.9 g ofbis(4-trifluoromethylphenyl)bromomethane are obtained in the form of abrown oil.

[0478] Bis(4-trifluoromethylphenyl)methanol is prepared according toPAVIA M. R. et al., J. Med. Chem., 4238 (1992).

EXAMPLE 46

[0479] On carrying out the operation according to Example 38 (Method 2),starting with 3.16 g of3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methyl-(RS)}azetidineand 0.96 g of ground sodium hydroxide, a yellow foam is obtained, after16 hours at room temperature, which is chromatographed on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 4.8 cm, height 14 cm), atan argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (15/85 by volume) as eluent and collecting 40 cm³ fractions.1.49 g of1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis-(trifluoromethyl)phenyl](methylsulfonyl)methylene}-azetidineare thus obtained in the form of a white foam [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 3.05 (3H, s, SCH₃), 3.90 (2H, s, NCH₂), 4.30(2H, s, NCH₂), 4.80 (1H, s, NCH), 7.40 (2H, d, J=7 Hz, 2CH arom.), 7.50(2H, d, J=7 Hz, 2CH arom.), 8.10 (2H, s, 2CH arom.), 8.20 (1H, s, CHarom.)].

[0480]3-Acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)-methyl-(RS)}azetidinemay be obtained in the following manner: on carrying out the operationas in Example 40 starting with 2.0 g of[3,5-bis(trifluoromethyl)benzyl]methylsulfone, 4.1 cm³ of a 1.6 Nsolution of n-butyllithium in hexane, 2.0 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 0.77 Cm³ of acetylchloride in 20 cm³ of anhydrous diisopropyl ether, 3.56 g of3-acetoxy-1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis(trifluoromethyl)phenyl](methylsulfonyl)methyl-(RS)}azetidineare obtained in the form of a white foam after chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 5.6 cm, height16 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (1/9 by volume) as eluent and collecting 100 Cm³fractions.

[0481] [3,5-Bis(trifluoromethyl)benzyl]methylsulfone is prepared in thefollowing manner: on carrying out the operation according to Example 10starting with 1.8 g of 3,5-bis(trifluoromethyl)benzyl chloride and 1.22g of sodium methanesulfinate, 1.86 g of[3,5-bis-(trifluoromethyl)benzyl]methylsulfone are obtained in the formof a white solid.

EXAMPLE 47

[0482] On carrying out the operation as in Example 38 (Method 1),starting with 0.27 g of the mixture of the two diastereoisomers1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-oland after chromatography on a silica gel column (particle size 0.04-0.06mm, diameter 2.4 cm, height 7.5 cm), at an argon pressure of 0.5 barwith a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 20 cm³ fractions, 0.10 g of(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (250 MHz): 3.02 (3H, s, SCH₃), 3.82 (1H, dd, J=3 and 16Hz, NCHH), 4.04 (1H, dd, J=3 and 16 Hz, NCHH), 4.10 (1H, dd, J=3 and 16Hz, NCHH), 4.35 (1H, dd, J=3 and 16 Hz, NCHH), 5.12 (1H, s, NCH), 7.18(2H, d, J=8 Hz, 2CH arom.), 7.32 (1H, t, J=8 Hz, CH arom.), 7.38 (2H, d,J=7 Hz, 2CH arom.), 7.45 (2H, d, J=7 Hz, 2CH arom.), 7.48 (1H, dd, J=2and 7 Hz, CH arom.), 7.58 (1H, d, J=2 Hz, CH arom.), 7.80 (1H, d, J=7Hz, CH arom.)].

[0483] The mixture of the two diastereoisomers1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to Example 39 starting with 0.56 g of(RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane and 0.50 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.0 cm, height 13 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 byvolume) as eluent and collecting 40 cm³ fractions, fractions 9 to 14 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.27 g of the mixture of the two diastereoisomers1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl-(RS)]-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained.

[0484] (RS)-bromo(4-chlorophenyl)(2,4-dichlorophenyl)methane may beprepared according to the procedure described by BACHMANN W. E., J. Am.Chem. Soc. , 2135 (1933) starting with 4.05 g of(RS)-(4-chlorophenyl)(2,4-dichlorophenyl)methanol, 10 cm³ of 33%hydrobromic acid in acetic acid and 2.1 cm³ of acetyl bromide. 4.6 g of(RS)-bromo(4-chlorophenyl)-(2,4-dichlorophenyl)methane are obtained inthe form of a greenish oil.

[0485] (RS)-(4-chlorophenyl)(2,4-dichlorophenyl)methanol is preparedaccording to PAVIA M. R. et al., J. Med. Chem., 4238 (1992).

EXAMPLE 48

[0486] 75.6 cm³ of 5 N hydrochloric acid are added to a solution of 18.9g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 80 cm³ of tetrahydrofuran. After 3 hours at room temperature, themixture is taken up in dichloromethane and distilled water and thenadjusted to pH 14 by addition of 30% sodium hydroxide and separatedafter settling out. The organic phase is washed twice with 100 cm³ ofwater and then 100 cm³ of a saturated aqueous sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). 16 g of(RS)-1-[(4-chlorophenyl)-(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidineare obtained in the form of a white foam [Spectrum in DMSO-d₆, T=300K, δin ppm (300 MHz): 3.06 (3H, s, SCH₃), 3.95 (2H, m, NCH₂), 4.26 (2H, m,NCH₂), 4.91 (1H, s, NCH), 7.20 (2H, d, J=8 Hz, 2CH arom.), 7.36 (1H, t,J=8 Hz, 1CH arom.), 7.40 and 7.52 (4H, 2d, J=7.5 Hz, 4CH arom.), 7.70and 7.88 (4H, 2d, J=7.5 Hz, 4CH arom.), 9.97 (1H, s, CH aldehydic)].

[0487]1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)-phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemay be prepared according to the following method: 13.0 cm³ of1,8-diazabicyclo[5.4.0]undec-7-ene are added dropwise to a solution of34.45 g of the mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidinein 400 cm³ of tetrahydrofuran under argon at 0° C., and after customarytreatment, 16.6 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidineare obtained in the form of a white solid after chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 10.2 cm, height23 cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetateand cyclohexane (2/8 by volume) as eluent and collecting 250 cm³fractions.

[0488] The mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidinemay be obtained in the following manner: on carrying out the operationaccording to Example 40, starting with 11.6 g of(3,5-difluorobenzyl)methylsulfone, 35.1 cm³ of a 1.6 N solution ofn-butyllithium in hexane, 19.3 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-oneand 8.8 cm³ of acetyl chloride in 500 cm³ of tetrahydrofuran, 37.8 g ofthe mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)-[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidineare obtained in the form of a white foam.

[0489]1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-onemay be prepared in the following manner: 46 Cm³ of triethylamine areadded at room temperature to a solution of 28.32 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-olin 200 cm³ of dimethyl sulfoxide, and then a solution of 34 g of sulfurtrioxide-pyridine complex in 100 cm³ of dimethyl sulfoxide are addeddropwise. After 0.25 hour at room temperature, the reaction mixture ispoured over ice, extracted with ethyl acetate, washed with 3 times 400cm³ of water and then with 400 cm³ of a saturated sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure (2.7 kPa). The residue obtained ischromatographed on a silica gel column (particle size 0.04-0.06 mm,diameter 9.2 cm, height 21 cm), at an argon pressure of 0.5 bar with amixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent andcollecting 250 cm³ fractions. Fractions 9 to 18 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 20.4 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}azetidin-3-oneare obtained in the form of a yellow oil.

[0490]1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)-phenyl]methyl-(RS)}azetidin-3-olmay be prepared according to the procedure described by KATRITZKY A. R.et al., J. Heterocycl. Chem., 271 (1994) starting with 35.0 g of{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)-phenyl]methyl}amine, 8.3 g ofepibromohydrin, 5.1 g of sodium hydrogen carbonate and 400 cm³ ofethanol. 30.3 g of1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]-methyl-(RS)}azetidin-3-olare isolated.

[0491] {(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)-phenyl]methyl-(RS)}aminehydrochloride may be prepared according to the method described byGRISAR M. et al., J. Med. Chem., 885 (1973) starting with 67.2 g of4-(1,3-dioxolan-2-yl)benzonitrile, 88.2 g of 1-bromo-4-chlorobenzene, 11g of magnesium and 600 cm³ of ethyl ether. 42.3 g of{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(RS)}amine areobtained in the form of a yellow oil.

EXAMPLE 49

[0492] 0.020 g of sodium borohydride is added to a solution of 0.50 g of(RS)-1-{(4-chlorophenyl)-(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 15 cm³ of methanol at 0° C. After 1 hour at 0° C. , 40 cm³ of waterare added and the product extracted with 100 cm³ of dichloromethane. Theorganic phase is washed twice with 40 cm³ of water and then 40 cm³ of asaturated sodium chloride solution, dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is chromatographed on a silica gel column (particlesize 0.04-0.06 mm, diameter 3.2 cm, height 14 cm), at an argon pressureof 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 byvolume) and collecting 20 cm³ fractions. Fractions 20 to 25 are combinedand then concentrated to dryness under reduced pressure (2.7 kPa). 0.29g of(RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white foam [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (250 MHz): 3.02 (3H, s, SCH₃), 3.90 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.42 (2H, d, J=5 Hz, OCH₂), 4.75 (1H, s, NCH), 5.10 (1H,t, J=5 Hz, OH), between 7.10 and 7.50 (11H, m, 11CH arom.)].

EXAMPLE 50

[0493] 0.75 g of(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineand then 0.68 g of sodium triacetoxyborohydride are added to a solutionof 0.10 g of pyrrolidine in 20 cm³ of 1,2-dichloroethane. After 20 hoursat room temperature, 2 cm³ of 1 N sodium hydroxide are added, theproduct is extracted with 100 cm³ of dichloromethane, the organic phaseis washed twice with 50 cm³ of water and then 50 cm³ of a saturatedsodium chloride solution, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of0.5 bar with acetate as eluent and collecting 20 cm³ fractions.Fractions 10 to 18 are combined and then concentrated to dryness underreduced pressure (2.7 kPa). 0.39 g of(RS)-1-{(4-chlorophenyl)-[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white foam [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 1.65 (4H, m, 2CH₂), 2.40 (4H, m, 2NCH₂),3.02 (3H, s, SCH₃), 3.50 (2H, s, NCH₂Ph), 3.85 (2H, s, NCH₂), 4.20 (2H,s, NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.40 (9H, m, 9CH arom.),7.48 (2H, d, J=7 Hz, 2CH arom.)].

EXAMPLE 51

[0494] On carrying out the operation as in Example 50 starting with 0.93cm³ of a 2 M solution of dimethylamine in methanol, 30 cm³ of1,2-dichloroethane, 0.75 g of(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineand then 0.9 g of sodium triacetoxyborohydride, there is obtained afterchromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 17.5 cm), at an argon pressure of 0.5 bar with amixture of ethyl acetate and cyclohexane (30/70 by volume) as eluent andcollecting 40 cm³ fractions, 0.46 g of(RS)-1-[(4-chlorophenyl)(4-dimethylaminomethyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidinein the form of a white solid [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 2.12 (6H, s, N(CH₃)₂), 3.02 (3H, s, SCH₃), 3.32 (2H, s,NCH₂Ph), 3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.18(2H, d, J=8 Hz, 2CH arom.), 7.22 (2H, d, J=8 Hz, 2CH arom.), 7.35 (1H,t, J=8 Hz, CH arom.), 7.39 (4H, m, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4CHarom.)].

EXAMPLE 52

[0495] A solution of 0.5 g of(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 10 cm³ of dichloromethane at 0° C. is stirred with 0.5 cm³ of asolution (2 M) of dimethylamine in ethanol. 13 mg ofhydroxybenzotriazole, 0.2 g of1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride and 0.18 cm³of diisopropylethylamine are then added. After 20 hours at roomtemperature, the reaction mixture is diluted with dichloromethane,washed twice with 80 cm³ of water and then 80 cm³ of a saturated sodiumchloride solution, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 4.1 cm, height 13 cm), at an argon pressure of0.5 bar with a dichloromethane/acetonitrile/methanol (98/1/1 by volume)mixture as eluent and collecting 15 cm³ fractions. Fractions 13 to 15are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.16 g of a cream-colored solid is obtained which, aftertaking up in isopropyl ether and drying, gives 0.11 g of(RS)-1-{(4-chlorophenyl)[4-N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine in the form of a solid [NMR spectrumin DMSO-d₆, T=300K, δ in ppm (300 MHz): 2.85 (3H, broad s, NCH₃), 2.95(3H, broad s, NCH₃), 3.00 (3H, s, SCH₃), 3.90 (2H, s, NCH₂), 4.20 (2H,s, NCH₂), 4.80 (1H, s, NCH), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (1H,t, J=8 Hz, CH arom.), 7.35 (4H, m, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CHarom.)].

[0496] (RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: 1.0 cm³ of Jones reagent isadded to a solution of 0.50 g of(RS)-1-{(4-chlorophenyl)(4-formylphenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 10 cm³ acetone at 0° C. After 5 hours, the reaction mixture is pouredinto distilled water, the product is extracted with 50 cm³ of ethylacetate, the organic phase is washed twice with 50 cm³ of water and then50 cm³ of a saturated sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from an ethylacetate-cyclohexane mixture, filtered and dried. 0.50 g of(RS)-1-{(4-carboxyphenyl)(4-chlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidineis obtained in the form of a white solid.

EXAMPLE 53

[0497] The operation is carried out as in Example 52, starting with 1 gof(RS)-1-{(4-carboxyphenyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,0.38 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22mg of hydroxybenzotriazole hydrate, 30 cm³ of dichloromethane and 0.83cm³ of a 2 M ethylamine solution in THF, chromatographing on a silicagel column (particle size 0.04-0.06 mm, diameter 4.1 cm, height 15 cm),at an argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (45/55 by volume) as eluent and collecting 30 cm³ fractions.Fractions 22 to 32 are combined and then concentrated to dryness underreduced pressure (2.7 kPa). 0.29 g of(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 1.07 (3H, t, J=6 Hz, CH₃), 3.00 (3H, s,SCH₃), 3.35 (2H, m, NCH₂), 3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80(1H, s, NCH), 7.15 (2H, d, J=8 Hz, 2CH arom.), 7.30 (1H, t, J=8 Hz, CHarom.), 7.35 (2H, d, J=7 Hz, 2CH arom.), 7.48 (4H, m, 4CH arom.), 7.74(2H, d, J=7 Hz, 2CH arom.), 8.37 (1H, t, CONH)].

EXAMPLE 54

[0498] The operation is carried out as in Example 52, starting with 1 gof(RS)-1-{(4-carboxyphenyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,0.38 g of 1,3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 22mg of hydroxybenzotriazole hydrate, 40 cm³ of dichloromethane and 0.24cm³ of a 7 N solution of ammonium hydroxide in methanol andchromatographing on a silica gel column (particle size 0.04-0.06 mm,diameter 4.1 cm, height 15 cm), at an argon pressure of 0.5 bar with amixture of ethyl acetate and cyclohexane (60/40 by volume) as eluent andcollecting 35 cm³ fractions. Fractions 38 to 48 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.29 g of asolid is obtained which, after taking up in isopropyl ether and drying,gives 0.22 g of(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein the form of a white solid [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(300 MHz): 3.00 (3H, s, SCH₃, 3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂),4.82 (1H, s, NCH), 7.17 (2H, d, J=8 Hz, 2CH arom.), 7.30 (1H, t, J=8 Hz,CH arom.), 7.38 (2H, d, J=7 Hz, 2CH arom.), 7.50 (5H, m, 4CH arom. and 2CONH₂), 7.80 (2H, d, J=7 Hz, 2CH arom.), 7.90 (1H, s, 2 CONH₂)].

EXAMPLE 55

[0499] The operation is carried out according to the procedure ofExample 4 starting with 1.7 g of1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.35 cm³ of methanesulfonyl chloride and 1.5 g of4-dimethylaminopyridine. The residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 35 cm), at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol (99.5/0.5 by volume) as eluentand collecting 100 cm³ fractions. Fractions 7 to 10 are combined andthen concentrated to dryness under reduced pressure (2.7 kPa). The solidis crystallized from 15 cm³ of ethyl ether. 0.2 g of1-[bis(4-chloro-phenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained melting at 200° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (6H, m,6CH arom.), 7.67 (1H, s, CH arom.)].

[0500]1-[Bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 39 starting with 4 g ofbis(4-chlorophenyl)bromomethane and 3 g of3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride, the residue obtained is purified by chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 40cm), at a nitrogen pressure of 0.5 bar with dichloromethane and then amixture of dichloromethane and ethanol (99/1 by volume) as eluent andcollecting 100 cm³ fractions. Fractions 15 to 19 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 1.7 g of1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

[0501] Bis(4-chlorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).3-[(3,5-Dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride may be obtained in the following manner: on carrying outthe operation according to the procedure of Example 39 starting with 5.6g of3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-oland 56 cm³ of a 6.2 N solution of hydrochloric dioxane in 56 cm³ ofdioxane, 5.1 g of 3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol hydrochloride are obtained in the form of a foam.

[0502]3-[(3,5-Dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olmay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 39 starting with 7.4 g of1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-oland 1.6 cm³ of vinyl chloroformate in 75 cm³ of dichloromethane, theresidue obtained is purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 3 cm, height 40 cm), at a nitrogenpressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane(30/70 by volume) as eluent and collecting 100 cm³ fractions. Fractions4 to 10 are combined and concentrated to dryness under reduced pressure(2.7 kPa). 5.6 g of3-[(3,5-dichlorophenyl)(methylsulfonyl)methyl-(RS)]-1-(vinyloxycarbonyl)-azetidin-3-olare obtained in the form of a foam.

EXAMPLE 56

[0503] On carrying out the operation according to the procedure ofExample 4 starting with 0.5 g of1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.1 cm³ of methanesulfonyl chloride and 0.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol (98/2 by volume) as eluent andcollecting 20 cm³ fractions. Fractions 8 to 13 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 8 cm³ of ethyl ether. 0.3 g of1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methylene]azetidineis obtained melting at 176° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (250 MHz): 2.90 (6H, s, N(CH₃)₂), 2.95 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 6.70 (3H, m, 3CH arom.),7.20 (3H, m, 3CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.48 (4H, d,J=7 Hz, 4CH arom.)].

[0504]1-Benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 0.4 g of(3-dimethylaminobenzyl)methylsulfone, 0.4 g of1-benzhydrylazetidin-3-one and 1.2 cm³ of a 1.6 M solution ofn-butyllithium in hexane, 0.5 g of1-benzhydryl-3-[(3-dimethylaminophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained in the form of a solid melting at 185° C.

[0505] (3-Dimethylaminobenzyl)methylsulfone may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 2 starting with 1.4 g of(3-dimethylaminobenzyl)methylsulfide and 5.1 g of oxone^(R), 1.1 g of(3-dimethylaminobenzyl)methylsulfone are obtained in the form of a whitesolid melting at 195° C.

[0506] (3-Dimethylaminobenzyl)methylsulfide may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 37 starting with 4 g of(3-iodobenzyl)methylsulfide, 1.4 g of dimethylamine in solution in 5 cm³of tetrahydrofuran, 2.9 g of sodium tert-butoxide, 0.56 g of1,1-bis(diphenylphosphino)ferrocenylpalladium chloride and 1.3 g of1,1′-bis(diphenylphosphino)ferrocene in 35 cm³ of tetrahydrofuran, 0.9 gof (3-dimethylaminobenzyl)methylsulfide is obtained in the form of anoil.

EXAMPLE 57

[0507] On carrying out the operation according to the procedure ofExample 4 starting with 1.3 g of1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 1.4 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol (98/2 by volume) as eluent andcollecting 20 cm³ fractions. Fractions 11 to 13 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 15 cm³ of ethyl ether. 0.6 g of1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]-azetidineis obtained melting at 146° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 2.45 (3H, s, PhSCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), between 7.10 and 7.50(14H, m, 14CH arom.)].

[0508]1-Benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 1.1 g ofmethyl(3-methylsulfanylbenzyl)sulfone, 1.2 g of1-benzhydrylazetidin-3-one, 1.3 g of1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a solid.

[0509] Methyl(3-methylsulfanylbenzyl)sulfone may be prepared in thefollowing manner: a mixture of 5 g of (3-iodobenzyl)methylsulfone and 1g of tetrakis-triphenylphosphinepalladium in 250 cm³ of dimethylsulfoxide is heated at a temperature close to 100° C. , under a nitrogenstream, for 1 hour. 2.5 g of sodium methylthiolate are added and thenthe heating at 100° C. is maintained for 18 hours. The reaction mediumis cooled to room temperature and taken up in 700 cm³ of ethyl acetateand 500 cm³ of water. The organic phase is decanted off, washed with 10times 500 cm³ of water, 500 cm³ of a saturated aqueous sodium chloridesolution, filtered on sintered glass and concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with amixture of cyclohexane and ethyl acetate (70/30 and then 60/40 and then50/50 by volume) as eluent and collecting 30 cm³ fractions. Fractions 26to 30 are combined and concentrated to dryness under reduced pressure(2.7 kPa). 1.2 g of methyl(3-methylsulfanylbenzyl)methylsulfone areobtained in the form of an oil .

EXAMPLE 58

[0510] 4 cm³ of a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran are added to a solution, cooled to 5° C. , of 1.1 g1-benzhydryl-3-{[3-(tert-butyl-dimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}-azetidine in 10 cm³ of tetrahydrofuran. Themixture is stirred for 3 hours at a temperature close to 20° C. and thentaken up in 100 cm³ of ethyl acetate and twice 50 cm³ of water. Theorganic phase is decanted off, extracted, dried over anhydrous magnesiumsulfate and concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), at anitrogen pressure of 0.5 bar with a mixture of dichloromethane andethanol (95/5 by volume) as eluent and collecting 60 cm³ fractions.Fractions 4 to 6 are combined and concentrated to dryness under reducedpressure (2.7 kPa). 0.5 g of1-benzhydryl-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white solid melting at 152° C. [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH₃),3.80 (2H, s, NCH₂), 4.20 (2H, s, NC H₂), 4.50 (2H, d, J=5 Hz, OCH₂),4.75 (1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.20 (2H, t, J=7 Hz, 2CHarom.), 7.30 (8H, m. 8CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].

[0511]1-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methylene}-azetidinemay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 1.6 g of1-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.3 cm³ of methanesulfonyl chloride and 1.4 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 30 cm), at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 60 cm³ fractions. Fractions 15to 30 are combined and concentrated to dryness under reduced pressure(2.7 kPa). 1.1 g of1-benzhydryl-3-{[3-(tert-butyldimethylsiloxymethyl)phenyl](methylsulfonyl)methylene}-azetidineare obtained in the form of a white solid melting at 148° C.

[0512]1-Benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2 g of[3-(tert-butyldimethylsilyloxymethyl)benzyl]methylsulfone and 1.5 g of1-benzhydrylazetidin-3-one, 1.6 g of1-benzhydryl-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid melting at 175° C.

[0513] [(3-(Tert-butyldimethylsilyloxymethyl)benzyl]methylsulfone may beprepared in the following manner: a mixture of 13.4 g of(3-hydroxymethylbenzyl)methylsulfone, 11 g of imidazole and 12 g oftert-butyldimethylsilane chloride is stirred for 18 hours at atemperature close to 20° C. The solution is concentrated to drynessunder reduced pressure (2.7 kPa). The residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 5 cm, height 50 cm), at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 7to 14 are combined and concentrated to dryness under reduced pressure(2.7 kPa). 5.7 g of[3-(tert-butyl-dimethylsilyloxymethyl)benzyl]methylsulfone are obtainedin the form of a white solid melting at 80° C.

[0514] (3-Hydroxymethylbenzyl)methylsulfone may be prepared in thefollowing manner: a mixture of 26 g of 3-(methylsulfonylmethyl)benzoicacid and 4.6 g of lithium aluminium hydride in 600 cm³ oftetrahydrofuran is stirred for 18 hours at a temperature close to 20° C.The solution is cooled to 0° C. and then 15 cm³ of ethyl acetate, 5 cm³of water, 5 cm³ of a 15% aqueous solution of sodium hydroxide andfinally 30 cm³ of water are added successively. The mixture is filteredon celite, the filtrate taken up in 600 cm³ of ethyl acetate. Theorganic phase is taken up in 500 cm³ of water and then 200 cm³ of asaturated aqueous sodium chloride solution, decanted off, dried overanhydrous magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). 10.4 g of(3-hydroxymethylbenzyl)methylsulfone are obtained in the form of a gum.

[0515] 3-(Methylsulfonylmethyl)benzoic acid may be prepared in thefollowing manner: on carrying out the operation according to theprocedure of Example 10 starting with 23.3 g of 3-chloromethylbenzoicacid and 23.3 g of sodium methanesulfinate, 26 g of3-(methylsulfonylmethyl)benzoic acid are obtained in the form of a whitesolid melting at 210° C.

EXAMPLE 59

[0516] 0.13 g of sodium methylthiolate is added, while the temperatureis maintained below 30° C., to a solution of 0.8 g of1-benzhydryl-3-[(3-bromomethylphenyl)(methylsulfonyl)methylene]azetidinein 8 cm³ of dimethylformamide. The mixture is stirred for 18 hours at atemperature close to 20° C. and then taken up in 30 cm³ of ethyl acetateand 50 cm³ of water. The organic phase is decanted off, extracted andwashed with 3 times 50 cm³ of water, dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is purified by chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 2 cm, height 28 cm) at a nitrogen pressureof 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10 byvolume) as eluent and collecting 50 cm³ fractions. Fractions 8 to 14 arecombined and concentrated to dryness under reduced pressure (2.7 kPa).0.3 g of1-benzhydryl-3-{[3-(methylsulfanylmethyl)phenyl](methylsulfonyl)methylene]}azetidineis obtained in the form of a white solid melting at 150° C. [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 1.95 (3H, s, SCH₃),2.95 (3H, s, SCH₃), 3.75 (2H, s, SCH₂), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.75 (1H, s, NCH), 7.20 (2H, t, J=7 Hz, CH arom.), 7.30 (8H, d,J=7 Hz, 8CH arom.), 7.45 (4H, d, J=7 Hz, 4 CH arom.)].

[0517]1-Benzhydryl-3-[(3-bromomethylphenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: 0.23 cm³ of phosphorustribromide and then a drop of pyridine are added, at a temperature closeto 20° C., to a mixture of 1 g of1-benzhydryl-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]-azetidinein 10 cm³ of dichloromethane. The stirring is maintained for 18 hours atthe same temperature. The reaction medium is taken up in 20 Cm³ of waterand 10 cm³ of a saturated aqueous sodium chloride solution. The organicphase is decanted off, extracted, dried over anhydrous magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kPa). 1 g of1-benzhydryl-3-[(3-bromomethylphenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a foam used in the crude state in subsequentsyntheses.

EXAMPLE 60

[0518] On carrying out the operation according to the procedure ofExample 4 starting with 6.6 g of1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]azetidin-3-ol,1.7 cm³ of methanesulfonyl chloride and 5.2 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 6.5 cm, height 35 cm), at a nitrogen pressure of 0.5 bar with adichloromethane and methanol mixture (95/5 by volume) as eluent andcollecting 40 cm³ fractions. Fractions 7 to 15 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is crystallized from 100 cm³ of ethyl ether. 4.4 g of1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)-methylene]azetidine areobtained melting at 212° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm(250 MHz): 3.15 (3H, s, SCH₃), 3.55 (2H, broad s, NCH₂), 4.30 (2H, s,NCH₂), 4.70 (1H, s, NCH), 7.18 (2H, t, J=7 Hz, 2CH arom.), 7.25 (4H, t,J=7 Hz, 4CH arom.), 7.43 (4H, d, J=7 Hz, 4 CH arom.), 7.62 (2H, m, 2CHquinoline), 7.75 (1H, dd, J=2 and 7 Hz, CH quinoline), 8.05 (1H, dd, J=2and 7 Hz, CH quinoline), 8.43 (1H, dd, J=2 and 8 Hz, CH quinoline), 9.00(1H, dd, J=2 and 5 Hz, CH quinoline)].

[0519]1-Benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 5.5 g ofmethyl(quinol-8-ylmethyl)sulfone, 5.9 g of 1-benzhydrylazetidin-3-oneand 18.8 cm³ of a 1.6 M solution of n-butyllithium in hexane, 6.6 g of1-benzhydryl-3-[(methylsulfonyl)(quinol-8-yl)methyl-(RS)]azetidin-3-olare obtained in the form of a beige solid.

[0520] Methyl(quinol-8-ylmethyl)sulfone may be prepared in the followingmanner: on carrying out the operation according to the procedure ofExample 10 starting with 4.5 g of 8-chloromethylquinoline and 4.4 g ofsodium methanesulfinate, 5.7 g of methyl(quinol-8-ylmethyl)sulfone areobtained in the form of a beige solid.

[0521] 8-Chloromethyl quinoline may be prepared in the following manner:6.7 g of N-chlorosuccinimide and then 250 mg of benzoyl peroxide areadded, at a temperature close to 20° C., to a mixture of 7.1 g of8-methylquinoline in 250 cm³ of carbon tetrachloride. The reactionmedium is heated at the reflux temperature of the solvent for 36 hoursand then cooled to 200C. The mixture is filtered on sintered glass andthe filtrate is concentrated to dryness under reduced pressure (2.7kPa). The residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 5.5 cm, height 32 cm), at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 40 cm³ fractions. Fractions 21 to 40 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 4.5 g of8-chloromethylquinoline are obtained in the form of a brown oil which isused in the crude state in subsequent syntheses.

EXAMPLE 61

[0522] On carrying out the operation according to the procedure ofExample 4 starting with 6.2 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,1.4 cm³ of methanesulfonyl chloride and 6.1 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm, height 60 cm), at a nitrogen pressure of 0.5 bar withdichloromethane as eluent and collecting 100 cm³ fractions. Fractions 4to 7 are combined and concentrated to dryness under reduced pressure(2.7 kPa). The solid obtained is crystallized from 25 cm³ of ethylether. 0.7 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a solid melting at 178° C. [NMR spectrum inDMSO-d6, T=300K, δ in ppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s,NCH₂)₁ 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), 7.30 (4H, d, J=7 Hz, 4CHarom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 7.60 (1H, t, J=7 Hz, CH arom.),7.70 (1H, d, J=7 Hz, CH arom.), 7.85 (2H, m, 2CH arom.)].1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 5.5 g of(3-cyanophenyl)methylsulfone, 6.1 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 13.8 cm³ of a 1.6 Msolution of n-butyllithium in hexane, 6.3 g of1-[bis-(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a foam.

EXAMPLE 62

[0523] A mixture of 4.5 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]-azetidinein 50 cm³ of acetic acid and 50 cm³ of concentrated hydrochloric acid(d=1.18) is heated at 50° C. for 20 hours. The reaction medium is cooledto room temperature and concentrated to dryness under reduced pressure(2.7 kPa). The oil obtained is taken up in 100 cm³ of ethanol and thenthe solution is concentrated to dryness under reduced pressure (2.7kPa). The residue is precipitated in 60 cm³ of ethyl ether. The solidobtained is purified by chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 25 cm, height 40 cm) at a nitrogen pressureof 0.5 bar with dichloromethane and then a dichloromethane and ethanolmixture (99.5/0.5 by volume) as eluent and collecting 30 cm³ fractions.Fractions 35 to 46 are combined and concentrated to dryness underreduced pressure (2.7 kPa). The solid obtained is crystallized from 15cm³ of ethyl ether. 0.2 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a solid melting at 192° C. [NMR spectrum inDMSO-d₆, T=300K, δ in ppm (300 MHz): 2.95 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.35 (4H, d, J—7 Hz, 4CHarom.), 7.45 (5H, d, J=7 Hz, 4CH arom. and 2 CONH₂), 7.50 (2H, m, 2CHarom.), 7.85 (2H, m, 2CH arom.)].

EXAMPLE 63

[0524] On carrying out the operation according to the procedure ofExample 1 starting with 0.8 g of1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methyl-amino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol,0.2 cm³ of methanesulfonyl chloride and 0.7 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm), at a nitrogen pressure of 0.5 bar with adichloromethane and ethanol mixture (98/2 by volume) as eluent,collecting 20 cm³ fractions. Fractions 4 to 8 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). The solidobtained is recrystallized from 10 cm³ of ethyl acetate. 0.5 g of1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}-azetidineis obtained in the form of a solid melting at 161° C. [NMR spectrum inDMSO-d₆, T=300K, δ in ppm (300 MHz): 1.30 (9H, s, (CH₃)₃), 2.95 (3H, s,SCH₃), 3.15 (3H, s, NCH₃), 3.75 (2H, s, SCH₂), 3.80 (2H, s, NCH₂), 4.20(2H, s, NCH₂), 4.75 (1H, s, NCH), between 7.15 and 7.50 (14H, m, 14CHarom.)].

[0525]1-Benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 1.6 g of[3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone, 1.3 g of1-benzhydrylazetidin-3-one and 3.8 cm³ of a 1.6 M solution ofn-butyllithium in hexane, 0.8 g of1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}-azetidin-3-olis obtained in the form of a white solid.

[0526] [3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfonemay be prepared in the following manner: 2.5 g of di-tert-butyldicarbonate in 40 cm³ of dioxane are added to a solution, cooled to 0°C. of methyl(3-methylaminobenzyl)sulfone in 30 cm³ of dioxane. Thestirring is maintained for 18 hours at room 3 temperature. The reactionmedium is taken up in 75 cm of dichloromethane; the organic phase iswashed with 75 cm³ of water and then with 75 cm³ of a saturated aqueoussodium chloride solution. The organic phase is decanted off, extracted,dried over anhydrous sodium sulfate, filtered and concentrated todryness under reduced pressure (2.7 kPa). The residue obtained ispurified by chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 2 cm, height 35 cm) at a nitrogen pressure of 0.5bar with a cyclohexane and ethyl acetate mixture (50/50 by volume) aseluent, collecting 20 cm³ fractions. Fractions 5 to 10 are combined andconcentrated to dryness under reduced pressure (2.7 kPa). 1.8 g of[3-(N-tert-butyloxycarbonyl-N-methylamino)benzyl]methylsulfone areobtained in the form of a colorless oil.

[0527] Methyl(3-methylaminobenzyl)sulfone may be prepared in thefollowing manner: a mixture of 9.7 cm³ of formic acid (d=1.22) and 19.6cm³ of acetic anhydride (d=1.08) is heated for 3 hours at 50° C. andthen the solution is allowed to return to room temperature. 40 cm³ oftetrahydrofuran are added and the mixture is cooled to −20° C. 14.8 g of(3-aminobenzyl)methylsulfone and 200 cm³ of tetrahydrofuran are thenadded. The stirring is maintained for 2 hours at −20° C. and then 48hours at room temperature. The mixture is filtered on sintered glass,the precipitate is washed with 3 times 50 cm³ of disopropyl ether andthen dried. The filtrate is concentrated to half its volume (2.7 kPa),the precipitate obtained is filtered on sintered glass and washed with 3times 30 cm³ of diisopropyl ether and then dried. The two precipitatesare combined and dissolved in 375 cm³ of tetrahydrofuran. The solutionis cooled to 0° C. ; 100 cm³ of a 2 M solution of borane dimethylsulfide in tetrahydrofuran added and then heated under reflux for 3hours. The mixture is cooled to 5° C. and then 60 cm³ of methanol areadded over 20 minutes. The stirring is maintained for 1 hour at roomtemperature. A stream of hydrogen chloride is bubbled in the solutionfor 5 minutes. The reaction medium is then heated under reflux for 1hour, cooled to room temperature and taken up in 300 cm³ of water. Thesolution is alkalinized with 3N sodium hydroxide and then with asaturated aqueous sodium bicarbonate solution. The organic phase isextracted with twice 250 cm³ of ethyl acetate, washed with 300 cm³ of asaturated aqueous sodium bicarbonate solution and twice 300 cm³. It isconcentrated to dryness under reduced pressure (2.7 kPa). The oilobtained is taken up in 100 cm³ of 4 N hydrochloric acid and then with100 cm³ of ethyl acetate. The aqueous phase is alkalinized with 120 cm³of 3 N sodium hydroxide, and then with an aqueous sodium bicarbonatesolution. The organic phase is extracted with twice 75 cm³ of ethylacetate, dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2.7 kPa). 9 g ofmethyl(3-methylaminobenzyl)sulfone are obtained in the form of a pinksolid.

[0528] (3-Aminobenzyl)methylsulfone may be prepared in the followingmanner: a mixture of 23.7 g of methyl-(3-nitrobenzyl)sulfone, 65 cm³ ofhydrochloric acid (d=1.18) and 150 cm³ of methanol is heated underreflux for 15 minutes. 18.5 g of iron are added over 10 minutes and thereflux is maintained for 4 hours and then 18 hours at room temperature.The reaction medium is alkalinized with an aqueous solution of ammoniumhydroxide and then with an aqueous sodium bicarbonate solution. Theorganic phase is extracted with 3 times 250 cm³ of ethyl acetate, driedover magnesium sulfate, filtered on sintered glass and concentrated todryness under reduced pressure (2.7 kPa). 14.9 g of(3-aminobenzyl)methylsulfone are obtained in the form of a beige solidwhich is used in the crude state in subsequent syntheses.

EXAMPLE 64

[0529] A mixture of 0.3 g of1-benzhydryl-3-{[3-(N-tert-butyloxycarbonyl-N-methylamino) phenyl](methyl-sulfonyl)methylene}azetidine, 4 cm³ of a 4.7 N solution ofhydrochloric dioxane and 4 cm³ of dioxane is stirred for 18 hours atroom temperature. The reaction medium is concentrated to dryness underreduced pressure (2.7 kPa). The residue is taken up in 100 cm³ of waterand 20 cm³ of diethyl ether. The aqueous phase is alkalinized with 30cm³ of an aqueous sodium bicarbonate solution. The organic phase isextracted with twice 40 cm³ of ethyl acetate, washed with twice 30 cm³of water, decanted off, dried over anhydrous magnesium sulfate, filteredand concentrated to dryness under reduced pressure (2.7 kPa). Theresidue is crystallized from 20 cm³ of diethyl ether. 0.16 g of1-benzhydryl-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]-azetidineis obtained in the form of a solid melting at 161° C. [NMR spectrum inDMSO-d₆, T=300K, δ in ppm (250 MHz): 2.65 (3H, d, J=5 Hz, NCH₃), 2.95(3H, s, SCH₃) 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH),5.80 (1H, q, J=5 Hz, NH), 6.60 (3H, m, 3CH arom.), 7.15 (1H, t, J=7 Hz,CH arom.), 7.22 (2H, t, J=7 Hz, 2CH arom.), 7.30 (4H, t, J=7 Hz, 4CHarom.), 7.48 (4H, d, J=7 Hz, 4 CH arom.)].

EXAMPLE 65

[0530] On carrying out the operation according to the procedure ofExample 4 starting with 11.3 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-ol,2.6 cm³ of methanesulfonyl chloride and 10.9 g of4-dimethylamino-pyridine, 5 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidineare obtained after recrystallization from 20 cm³ of diethyl ether,melting at 181° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz):2.95 (3H, s, SCH₃), 3.77 (3H, s, OCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.80 (1H, s, NCH), 6.95 (3H, m, 3CH arom.), 7.35 (5H, m, 5CHarom.), 7.45 (4H, d, J=7 Hz, 4CH arom.)].1-[Bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 6.6 g of(3-methoxybenzyl)methylsulfone, 10 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 23 cm³ of a 1.6 Nsolution of n-butyllithium in hexane, 11.4 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a white solid melting at 130° C.

EXAMPLE 66

[0531] On carrying out the operation according to the procedure ofExample 32 starting with 4.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,32 cm³ of a 1 M solution of boron tribromide in dichloromethane, theresidue obtained is purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), at a nitrogenpressure of 0.5 bar with a mixture of dichloromethane and ethanol (98/2by volume) as eluent and collecting 20 cm³ fractions. Fractions 16 to 17are concentrated to dryness under reduced pressure (2.7 kPa). 0.1 g1-[bis(4-chloro-phenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)-methylene]azetidineis obtained, after recrystallization from 5 cm³ of diethyl ether, in theform of a solid melting at 114° C. [NMR spectrum in DMSO-d6, T=300K, δin ppm (250 MHz): 2.92 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.80 (1H, s, NCH), 6.80 (3H, m, 3CH arom.), 7.20 (1H, t, J=7 Hz,CH arom.), 7.37 (4H, t, J=7 Hz, 4CH arom.), 7.47 (4H, d, J=7 Hz, 4 CHarom.)].

EXAMPLE 67

[0532] On carrying out the operation according to the procedure ofExample 4 starting with 0.6 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-ol,0.1 cm³ of methanesulfonyl chloride and 0.5 g of4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 2 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with adichloromethane and ethanol mixture as eluent (98.5/1.5 by volume) andcollecting 10 cm₃ fractions. Fraction 4 is concentrated to dryness underreduced pressure (2.7 kPa). 0.5 g1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-pyrrolidinylphenyl)methylene]azetidineis obtained, after recrystallization from 5 cm³ of diethyl ether, in theform of a solid melting at 133° C. [NMR spectrum in DMSO-d₆, T=300K, δin ppm (400 MHz): 2.00 (4H, m, 2 CH₂), 2.95 (3H, s, SCH₃), 3.20 (4H, m,2 NCH₂), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 6.50(1H, s, CH arom.), 6.60 (1H, d, J=7 Hz, CH arom.), 6.65 (1H, d, J=7 Hz,CH arom), 7.20 (1H, t, J=7 Hz, CH arom.), 7.40 (4H, d, J=7 Hz, 4 CHarom.), 7.50 (4H, d, J=7 Hz, 4 CH arom.)].

[0533]1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 0.5 g ofmethyl-(3-pyrrolidinylbenzyl)sulfone, 0.6 g of1-[bis-(4-chlorophenyl)methyl]azetidin-3-one and 1.4 cm³ of a 1.6 Nsolution of n-butyllithium in hexane, 0.6 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-pyrrolidinylphenyl)methyl-(RS)]azetidin-3-olis obtained in the form of a cream-colored solid.

EXAMPLE 68

[0534] On carrying out the operation according to the procedure ofExample 58 starting with 5.1 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyl-dimethylsilyloxymethyl)phenyl](methylsulfonyl)-methylene}azetidineand 17 cm³ of a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran, the residue obtained is purified by chromatography on asilica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 30cm), at a nitrogen pressure of 0.5 bar with a dichloromethane andethanol mixture (97/3 by volume) as eluent and collecting 100 cm³fractions. Fractions 10 to 14 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). The yellow solid obtained is taken upin 2 cm³ of dichloromethane and 10 cm³ of ethyl acetate and thenfiltered on sintered glass and washed with 2 cm³ of ethyl acetate. 1.6 gof1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxy-methylphenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of a white solid melting at 214° C. [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (400 MHz): 2.95 (3H, s, SCH₃),3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.50 (2H, d, J=5 Hz, OCH₂), 4.80(1H, s, NCH), 5.25 (1H, t, J=5 Hz, OH), 7.30 (1H, d, J=7 Hz, CH arom.),between 7.35 and 7.45 (7H, m, 7CH arom.), 7.50 (4H, d, J=7 Hz, 4CHarom.)].

[0535]1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)-methylene}azetidinemay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 4 starting with 10.8 g of1-[bis-(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyl-oxymethyl)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol,2 cm³ of methanesulfonyl chloride and 8.5 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 4 cm, height 40 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 100 cm³ fractions. Fractions 12 to 29 are combined,concentrated to dryness under reduced pressure (2.7 kPa). 5.2 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methyl-sulfonyl)methylene}azetidineare obtained in the form of a gum.

[0536]1-[Bis(4-chlorophenyl)methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)phenyl](methylsulfonyl)-methyl-(RS)}azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 5.8 g of[3-(tert-butylsilyloxymethyl)benzyl]methyl-sulfone and 5.6 g of1-[bis(4-chlorophenyl)methyl]-azetidin-3-one, 10.8 g of1-[bis(4-chlorophenyl)-methyl]-3-{[3-(tert-butyldimethylsilyloxymethyl)-phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-olare obtained in the form of a gum.

EXAMPLE 69

[0537] A mixture of 0.45 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidine,0.07 cm³ of 1-aminopiperidine in 4 cm³ of dimethylformamide is stirredfor 18 hours at room temperature. The mixture is taken up in 30 cm³ ofethyl acetate. The organic phase is washed with 3 times 50 cm³ of water,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). 0.2 g of1-[bis-(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(N-piperidylcarbamoyl)phenyl]methylene}azetidineis obtained melting at 175° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (400 MHz): 1.40 (2H, m, CH₂), 1.60 (4H, m, 2CH₂), 2.85 (4H, m,2NCH₂), 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80(1H, s, NCH), between 7.45 and 7.60 (10H, m, 10CH arom.), 7.75 (2H, m,2CH arom.), 9.45 (1H, s, NH)].1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]-methylene}azetidinemay be prepared in the following manner: on carrying out the operationaccording to the procedure of Example 29 starting with 2.6 g of1-[bis-(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinehydrochloride, 0.9 g of pentafluorophenol, 0.9 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 25 cm³ ofdimethylformamide, the residue obtained is purified by chromatography ona silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height30 cm), at a nitrogen pressure of 0.5 bar with a mixture ofdichloromethane and ethanol (99/1 by volume) as eluent and collecting 30cm³ fractions. Fractions 7 to 12 are combined and concentrated todryness under reduced pressure (2.7 kPa). 0.9 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene}azetidineis obtained in the form of a foam.

[0538]1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: 2 cm³ of Jones reagent areadded to a mixture of 0.5 g of1-[bis-(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)-(methylsulfonyl)methylene]azetidinein 9 cm³ of acetone, cooled to 5° C. This stirring is maintained for 2hours at this temperature and then 50 cm³ of a mixture of water and iceand 50 cm³ of ethyl acetate are added. The organic phase is decantedoff, washed with 50 cm³ of a saturated aqueous sodium chloride solution,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (2.7 kPa). The residue obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 3 cm, height 25 cm), at a nitrogen pressure of 0.5 bar with amixture of dichloromethane and ethanol as eluent and collecting 60 cm³fractions. Fractions 12 to 14 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). The solid obtained is crystallizedfrom 10 cm³ of ethyl ether. 32 mg of1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]-azetidineare obtained in the form of a solid melting at 205° C. [NMR spectrum inDMSO-d₆, T=300K, δ in ppm (400 MHz): 2.90 (3H, s, SCH₃), 3.80 (2H, s,NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.33 (4H, d, J=7 Hz, 4CHarom.), 7.39 (1H, d, J=7 Hz, CH arom.), 7.42 (4H, d, J=7 Hz, 4CH arom.),7.49 (1H, t, J=7 Hz, CH arom.), 7.57 (1H, d, J=7 Hz, CH arom.), 7.90(2H, s, CH arom. and NH⁺)]

EXAMPLE 70

[0539] On carrying out the operation according to the procedure forExample 4 starting with 0.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-trifluoromethylsulfanylphenyl)methyl(RS)]azetidin-3-ol,0.24 g of methanesulfonyl chloride and 0.7 g of 4-dimethylaminopyridine,the residue obtained is purified by chromatography on a silica gelcolumn (particle size 0.04-0.06 mm, diameter 2 cm, height 18 cm) at anitrogen pressure of 0.5 bar with dichloromethane as eluent andcollecting 50 cm³ fractions. Fractions 12 to 17 are combined,concentrated to dryness under reduced pressure (2.7 kPa). The residueobtained is again purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), at a nitrogenpressure of 0.5 bar with dichloromethane as eluent and collecting 30 cm³fractions. Fractions 15 to 28 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). 0.25 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methylene]azetidineis obtained melting at 70° C. [NMR spectrum in DMSO-d₆+CD₃CO₂D, T=300K,δ in ppm (300 MHz): 3.00 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s,NCH₂), 4.80 (1H, s, NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (4H, d,J=7 Hz, 4 CH arom.), 7.60 (2H, m, 2CH arom), 7.75 (2H, m, 2CH arom.)].1-[Bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methyl-(RS)]-azetidin-3-olmay be obtained in the following manner: on carrying out the operationaccording to the procedure of Example 1 starting with 2 g ofmethyl-(3-trifluoromethylsulfanylbenzyl)sulfone, 2.3 g of1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.5 cm³ of a 1.6 Msolution of n-butyllithium in hexane, 0.9 g of1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethylsulfanylphenyl)methyl-(RS)]azetidin-3-olis obtained in the form of a white solid.

[0540] Methyl(3-trifluoromethylsulfanylbenzyl)sulfone may be prepared inthe following manner: on carrying out the operation according to theprocedure of Example 10 starting with 5 g of3-trifluoromethylsulfanylbenzyl chloride and 3.2 g of sodiummethanesulfinate, 5.2 g ofmethyl(3-trifluoromethylsulfanylbenzyl)sulfone are obtained in the formof a white solid melting at 125° C.

EXAMPLE 71

[0541] On carrying out the operation as in Example 38 (Method 1),starting with 0.72 g of1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.18 cm³ of methanesulfonyl chloride and 0.66 g of4-dimethylaminopyridine, 0.42 g of1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 2.5 cm, height 15 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 25 cm³ fractions, in the form of a white foam [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (250 MHz): 3.05 (3H, s, SCH₃),3.90 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.15 (6H, m,6CH arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.50 (4H, dd, J=6 and 8 Hz,4CH arom.)].

[0542]1-[Bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: the operation is carried out asin Example 39 starting with 2.25 g of bis(4-fluorophenyl)bromomethane,1.1 g of potassium carbonate and 2.5 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride. After chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4.4 cm, height 25 cm), at an argon pressureof 0.9 bar with a mixture of ethyl acetate and cyclohexane (2/8 byvolume) as eluent and collecting 60 cm³ fractions, fractions 23 to 39are combined and then concentrated to dryness under reduced pressure(2.7 kPa). 0.72 g of1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olis obtained in the form of a white solid.

[0543] Bis(4-fluorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc. , 2135 (1933)starting with 4 g of 4,4′-difluorobenzydrol, 2.70 cm³ of acetal bromideand 14 cm³ of a 33% hydrobromic acid solution in acetic acid.

EXAMPLE 72

[0544] On carrying out the operation as in Example 38 (Method 1),starting with 1.22 g of1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.29 cm³ of methanesulfonyl chloride and 1.1 g of4-dimethylaminopyridine, 0.177 g of1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 23 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 60 cm³ fractions, in the form of a white foam [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 3.05 (3H, s, SCH₃),3.95 (2H, s, NCH₂), 4.25 (2H, s, NCH₂), 5.35 (1H, s, NCH), 7.20 (6H, m,6CH arom.), 7.35 (3H, m, 3CH arom.), 7.55 (2H, m, 2CH arom.)].1-[Bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: the operation is carried out asin Example 39 starting with 2 g of bis(2-fluorophenyl)bromomethane, 1.0g of potassium carbonate and 2.22 g of3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olhydrochloride. After chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 3 cm, height 17 cm), at an argon pressure of1 bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) aseluent and collecting 60 cm³ fractions, fractions 6 to 10 are combinedand then concentrated to dryness under reduced pressure (2.7 kPa). 1.22g of1-[bis(2-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained in the form of a whitish solid.

[0545] Bis(2-fluorophenyl)bromomethane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc. , 2135 (1933),starting with 1.80 g of 2,2′-difluorobenzydrol, 1.22 cm³ of acetylbromide and 6.5 cm³ of a 33% solution of hydrobromic acid in aceticacid. 2,2′-difluorobenzydrol may be prepared according to the followingmethod: 32 cm³ of a 1.6 M solution of n-butyllithium in hexane arepoured dropwise into a solution, cooled to −70° C. under argon, of 8.8 gof 2-bromofluorobenzene in 100 cm³ of tetrahydrofuran. After stirringfor 10 minutes at −70° C. , 2.1 cm³ of ethyl formate are added slowlyand then the mixture is stirred at −70° C. for 30 minutes. The reactionmedium is then brought to 0° C. and then supplemented with 50 cm³ ofethyl acetate and 100 cm³ of saturated ammonium chloride solution. Afterstirring, the organic phase is separated, dried over magnesium sulfate,concentrated to dryness at 55° C., under reduced pressure (2.7 Kpa).3.63 g of 2,2′-difluorobenzydrol are obtained in the form of a yellowoil.

EXAMPLE 73

[0546] On carrying out the operation as in Example 38 (Method 1),starting with 1.15 g of1-[bis-(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.264 cm³ of methanesulfonyl chloride, and 0.98 g of4-dimethylaminopyridine, 0.55 g of1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 2.8 cm, height 25 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) aseluent and collecting 60 cm³ fractions, in the form of a white solidmelting at 178° C. [NMR spectrum in DMSO-d₆, T=300K, δ in ppm (250 MHz):3.05 (3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.25 (2H, s, NCH₂), 4.80 (1H, s,NCH), 7.10 (2H, m, 2CH arom.), 7.20 (2H, m, 2CH arom.), between 7.30 and7.50 (7H, m, 7CH arom.)].

[0547]1-[Bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be prepared in the following manner: on carrying out the operationaccording to Example 1 starting with 1.2 g of(3,5-difluorobenzyl)methylsulfone and 1.5 g of1-[bis(3-fluorophenyl)methyl]-azetidin-3-one, 1.95 g of1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained, after purification on a silica gel column (particle size0.06-0.200 mm, diameter 3.2 cm, height 30 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (2/8 by volume) aseluent and collecting 60 cm³ fractions, in the form of a white solidmelting at 170° C. (decomposition).1-[Bis(3-fluorophenyl)methyl]azetidin-3-one may be prepared by carryingout the operation in a manner identical to the procedure described byKATRITZKY A. R. et al., J. Heterocycl. Chem., 271 (1994), starting with4.9 g of [bis(3-fluorophenyl)methyl]amine and 1.78 cm³ ofepichlorohydrin. [Bis(3-fluorophenyl)methyl]amine may be prepared in thefollowing manner: a solution of 5.17 g of 3,3′-difluorobenzophenoneoxime in 30 cm³ of tetrahydrofuran is poured, under an argon atmosphereover 30 minutes, into a suspension of 1.27 g of lithium aluminum hydridein 80 cm³ of tetrahydrofuran. After stirring for 5 hours under reflux,1.3 cm³ of water, 1.3 cm³ of 4 N sodium hydroxide, 2.6 cm³ of water andthen 50 cm³ of ethyl acetate are added successively. After drying overmagnesium sulfate and concentrating to dryness under reduced pressure(2.7 kPa), 4.9 g of [bis(3-fluorophenyl)methyl]amine are obtained in theform of a yellow oil.

[0548] 3-3′-Difluorobenzophenone oxime may be prepared according to thefollowing procedure: a solution of 1.6 g of hydroxylamine hydrochloridein 8 cm³ of water is poured dropwise into a solution of 5.0 g of3,3′-difluorobenzophenone in 10 cm³ of ethanol, and then 1.2 g of sodiumhydroxide pellets are added in small fractions. The reaction mixture,heated under reflux for 10 minutes, is cooled to 20° C. and thenacidified with 7.5 cm³ of 4 N hydrochloric acid. Once triturated, theoily precipitate obtained becomes a white solid which is filtered,washed with water and then dried at 35° C. under reduced pressure (2.7kPa). 5.17 g of 3,3′-difluorobenzophenone oxime are obtained in the formof a white solid.

EXAMPLE 74

[0549] On carrying out the operation as in Example 1, starting with 1.30g of a mixture of two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol,0.35 cm³ of methanesulfonyl chloride and 1.22 g of4-dimethylaminopyridine, 0.7 g of(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 2.4 cm, height 25 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (1/1 by volume) aseluent and collecting 30 cm³ fractions, in the form of a pinkish solid[NMR spectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 2.95 (3H, s,SCH₃), 3.95 (2H, m, NCH₂), 4.35 (2H, m, NCH₂), 5.25 (1H, s, NCH), 7.45(9H, m, 9CH arom.), 7.65 (1H, d, J=2 Hz, CH thiazole), 7.70 (1H, d, J=2Hz, CH thiazole)].

[0550] The mixture of the two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationas in Example 39 starting with 4.47 g of(RS)-bromo(4-chlorophenyl)(thiazol-2-yl)methane and 4.31 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride andafter chromatography on a silica gel column (particle size 0.06-0.200mm, diameter 5.6 cm, height 40 cm), at an argon pressure of 0.5 bar witha mixture of ethyl acetate and cyclohexane (25/75 by volume) up tofraction 35 and then with pure ethyl acetate as eluent and collecting 60cm³ fractions, fractions 38 to 40 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 1.3 g of the mixture of thetwo diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olare obtained in the form of a whitish solid.(RS)-bromo(4-chlorophenyl)(thiazol-2-yl)methane may be preparedaccording to the procedure described by BACHMANN W. E., J. Am. Chem.Soc. , 2135 (1933), starting with 3.5 g of(RS)-(4-chlorophenyl)-(2-thiazolyl)methanol, 3.81 g of acetyl bromideand 12.0 cm³ of a 33% solution of hydrobromic acid in acetic acid.

[0551] (RS)-(4-chlorophenyl)(thiazol-2-yl)methanol may be preparedaccording to the procedure described by G. EVAN BOSWELL et al., J.Heterocyclic Chem., 32, 1801 (1995), starting with 4.22 g of4-chlorobenzaldehyde and 4.92 g of 2-bromothiazole.

EXAMPLE 75

[0552] On carrying out the operation as in Example 1, starting with 0.52g of a mixture of the two diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.14 cm³ of methanesulfonyl chloride and 0.49 g of4-dimethylaminopyridine, 0.32 g of(RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 2.4 cm, height 20 cm), at an argon pressure of0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 byvolume) as eluent and collecting 30 cm³ fractions, in the form of awhite solid melting at 176° C. [NMR spectrum in DMSO-d₆, T=300K, δ inppm (300 MHz): 2.98 (3H, s, SCH₃), 3.90 (2H, m, NCH₂), 4.20 (2H, s,NCH₂), 5.03 (1H, s, NCH), 6.85 (1H, dd, J=3 and 5 Hz, CH thiophene),7.08 (3H, m, 2CH arom. and 1CH thiophene), 7.22 (1H, t, J=8 Hz, CHarom.),7.32 (3H, m, 2CH arom. and 1CH thiophene), 7.40 (2H, d, J=7 Hz,2CH arom.)].

[0553] The mixture of the two diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be prepared in the following manner: on carrying out the operationas in Example 1 starting with 1.60 cm³ of 1.6 N n-butyllithium insolution in hexane, 0.83 g of (3,5-difluorobenzyl)methylsulfone and 1.06g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-one, 0.55 gof the mixture of diastereoisomers1-[4-chlorophenyl)(thien-2-yl)methyl-(RS)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olis obtained, after purification on a silica gel column (particle size0.06-0.200 mm, diameter 2.8 cm, height 30 cm), at an argon pressure of0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 byvolume) as eluent and collecting 40 cm³ fractions, in the form of anoff-white solid.1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-one may beprepared by carrying out the operation in the following manner: 3.04 cm³of dimethyl sulfoxide are poured over 10 minutes into a solution, cooledto −70° C. , of 1.83 cm³ of oxalyl chloride in 20 cm³ of dichloromethaneunder argon. After stirring for 30 minutes at −60° C. , a solution of5.2 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol in 80cm³ of dichloromethane is poured in over 20 minutes, the mixture isstirred for 3 hours at a temperature of between −60° and -70° C. andthen 9.12 cm³ of triethylamine are added. The mixture is then allowed toreturn to room temperature and then diluted with water. The organicphase is separated, dried over magnesium sulfate and then concentratedto dryness under reduced pressure. The residue is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 36cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (1/9 by volume) as eluent and collecting 60 cm³ fractions.3.3 g of 1-[(4-chlorophenyl)(thien-2-yl)-methyl-(RS)]zetidin-3-one areobtained in the form of a yellow oil which crystallizes at roomtemperature.

[0554] 1-[(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-azetidin-3-ol may beprepared in the following manner: 4.12 g of sodium bicarbonate are addedto a solution of 11.0 g of[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]-amine in 80 cm³ of ethanol.The mixture is heated at 65° C. and supplemented with 4.03 cm³ ofepibromohydrin. After stirring for 20 hours at 65° C., the cooledmixture is filtered and the filtrate concentrated to dryness underreduced pressure (2.7 Kpa). The residue is chromatographed on a silicagel column (particle size 0.06-0.200 mm, diameter 3.6 cm, height 32 cm),at an argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (25/75 by volume) as eluent and collecting 60 cm³ fractions.6.3 g of 1-[(4-chlorophenyl)(thien-2-yl)methyl-(RS)]azetidin-3-ol areobtained in the form of a pale yellow oil.

[0555] [(4-Chlorophenyl)(thien-2-yl)methyl-(RS)]-amine may be preparedin the following manner: a solution of 10.92 g of2-thiophenecarbonitrile in 80 cm³ of ethyl ether is poured slowly into asuspension, cooled to 10° C. , of 4-chlorophenylmagnesium bromide(prepared from 19.15 g of 4-bromochlorobenzene and 2.43 g of magnesium)in 120 cm³ of anhydrous ethyl ether. After refluxing for one hour, themixture is cooled to 10° C. , supplemented slowly with 40 cm³ ofmethanol and then filtered on supercel. 4.54 g of sodium borohydride areadded under argon and in small fractions over 15 minutes and then thereaction medium is stirred for 20 hours at 20° C. The mixture obtainedis diluted with ethyl acetate and then washed with water. The organicphase is dried over magnesium sulfate, concentrated to dryness at 50° C.under reduced pressure (2.7 kPa). The residue is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 5 cm, height 42cm), at an argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (4/6 by volume) as eluent and collecting 100 cm³ fractions.Fractions 6 to 12, concentrated to dryness, correspond to 13 g of iminein the form of a yellow oil which is taken up in 100 cm³ of methanol.The solution obtained is supplemented with 2.4 g of sodium borohydrideand stirred for one hour at 5° C. The mixture obtained is diluted withethyl acetate and then washed with water. The organic phase is driedover magnesium sulfate, concentrated to dryness at 50° C. under reducedpressure (2.7 Kpa). The residue is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 3.2 cm, height 40 cm), atan argon pressure of 0.5 bar with a mixture of ethyl acetate andcyclohexane (4/6 by volume) as eluent and collecting 60 cm³ fractions.11.0 g of [(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine are obtained inthe form of a yellow oil.

EXAMPLE 76

[0556] On carrying out the operation as described in Example 75,starting with 1.66 g of the mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-ol,50 cm³ of dichloromethane, 0.45 cm³ of methanesulfonyl chloride, and1.64 g of 4-dimethylaminopyridine, 0.6 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of white crystals melting at 136° C., [a]²⁰_(D=+)3.2° (c=0.5% in dichloromethane).

[0557] The mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)-methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)-methyl-(S*)]azetidin-3-olmay be prepared as described in Example 75, starting with 1.06 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one, 0.82 g of(3,5-difluorobenzyl)methylsulfone, 2.5 cm³ of 1.6 N solution ofn-butyllithium in hexane, and 25 cm³ of tetrahydrofuran. 1.7 g of themixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(R*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-olare obtained, after purification by chromatography, in the form of awhite solid.

[0558] (+)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-one may beprepared as described in Example 75, starting with 12.4 g of(+)-1-[(4-chlorophenyl) (thien-2-yl)methyl]azetidin-3-ol, 220 cm³ ofdichloromethane, 7.1 cm³ of dimethyl sulfoxide, 4.4 cm³ of oxalylchloride and 21.5 cm³ of triethylamine. 9.2 g of(+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one are obtained inthe form of a pale yellow oil crystallizing at 20° C.

[0559] (+)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]-azetidin-3-ol may beprepared as described in Example 75, starting with 16.1 g of(+)-[(4-chlorophenyl) (thien-2-yl)methyl]amine, 130 cm³ of ethanol,

[0560] 5.9 cm³ of epibromohydrin and 6.05 g of sodium bicarbonate. 11.5g of (+)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol areobtained, after purification by chromatography, in the form of acream-colored oil.

[0561] (+)-4-[(Chlorophenyl)(thien-2-yl)methyl]amine may be prepared inthe following manner: 73 g of D-(−)-tartaric acid are added to asolution of 109 g of [(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine in500 cm³ of methanol. The mixture is concentrated to dryness underreduced pressure (2.7 kPa). The foam obtained is taken up in 2.05 litersof an ethanol-water 90/10 by volume mixture. After stirring slowly for20 hours at 20° C., the crystalline suspension obtained is filtered, thecrystals washed with a minimum amount of the same mixture of solvents,and then dried. Another recrystallization is carried out under the sameconditions with 1.5 liters of the same mixture of solvents. 44.9 g ofcrystals of the acid tartrate of the amine are obtained. [a]20D=+10.3°(c=0.5% in dimethylformamide). This compound is recrystallized from 600cm³ of an ethanol-water 80/20 by volume mixture (the crystals arefiltered and washed with twice 30 cm³ of the same mixture of solventsand then drained) and then recrystallized under the same conditions with400 cm³ of an ethanol-water 78/22 mixture. 28.2 g of acid D-(−)-tartrateof (+)-[(4-chlorophenyl)thien-2-yl)methyl]amine are obtained in the formof white crystals [a]20D=+10.8° (c=0.5% in dimethylformamide).

[0562] This salt is taken up in 400 cm³ of a 1 N aqueous solution ofsodium hydroxide and with 100 cm³ of ethyl acetate. The organic phase isseparated, washed with 100 cm³ of water, dried over magnesium sulfateand then concentrated to dryness under reduced pressure (2.7 kPa). 16.1g of (+)-[(4-chlorophenyl)-(thien-2-yl)methyl]amine are obtained in theform of an oil which crystallizes at 20° C. [a]20D=+32.7° (c=0.5% indichloromethane).

EXAMPLE 77

[0563] On carrying out the operation as described in Example 75,starting with 1.30 g of the mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-ol,40 cm³ of dichloromethane, 0.35 cm³ of methanesulfonyl chloride and 1.28g of 4-dimethylaminopyridine, 0.97 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]zetidineis obtained in the form of white crystals melting at 135° C., [a]−3.4°(c=0.5% in dichloromethane).

[0564] The mixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]-azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-olmay be prepared as described in Example 75, starting with 1.06 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one, 0.82 g of(3,5-difluorobenzyl)methylsulfone, 2.5 cm³ of 1.6 N solution ofn-butyllithium in hexane, and 25 cm³ of tetrahydrofuran. 1.3 g of themixture of the two chiral diastereoisomers1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidin-3-oland1-[(4-chlorophenyl)(thien-2-yl)methyl-(S*)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidin-3-olare obtained after purification by chromatography in the form of a whitesolid. (−)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-one may beprepared as described in Example 75, starting with 11.4 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol, 200 cm³ ofdichloromethane, 4.0 cm³ of dimethyl sulfoxide, 4.0 cm³ of oxalylchloride and 19.5 cm³ of triethylamine. 8.3 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-one are obtained inthe form of a pale yellow oil crystallizing at 20° C.

[0565] (−)-1-[(4-Chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol may beprepared as described in Example 75, starting with 15.4 g of(−)-[(4-chlorophenyl)(thien-2-yl)methyl]amine, 120 cm³ of ethanol, 5.8cm³ of epibromohydrin and 5.8 g of sodium bicarbonate. 10.7 g of(−)-1-[(4-chlorophenyl)(thien-2-yl)methyl]azetidin-3-ol are obtained,after purification by chromatography, in the form of a cream-coloredoil.

[0566] (−)-[(4-Chlorophenyl)(thien-2-yl)methyl]amine may be prepared inthe following manner: 29 g of L-(+)-tartaric acid are added to asolution of 43 g of [(4-chlorophenyl)(thien-2-yl)methyl-(RS)]amine in200 cm³ of methanol. The mixture obtained crystallizes in 2 hours atroom temperature. The crystals are filtered, washed with twice 10 cm³ ofmethanol. Recrystallization is carried out with 500 cm³ of anethanol-water 80/20 by volume mixture, the crystals are filtered, washedwith twice 30 cm³ of the same mixture of solvents and then dried undervacuum at 45° C. A final recrystallization is carried out with 350 cm³of an ethanol-water 78/22 by volume mixture, allowing the mixture to bestirred for 20 hours at 20° C. The crystals obtained are drained, driedunder reduced pressure (2.7 kPa). 26 g of acid L-(+)-tartrate of (−)-[(4-chlorophenyl) (thien-2-yl)methyl]amine are obtained. [a]²⁰_(D=−)10.7° (c=0.5% in dimethylformamide).

[0567] This salt is taken up in 400 cm³ of a 1 N aqueous sodiumhydroxide solution and with 100 Cm³ of ethyl acetate. The organic phaseis separated, washed with 100 cm³ of water, dried over magnesium sulfateand then concentrated to dryness under reduced pressure (2.7 kPa). 15.4g of (−)-[(4-chlorophenyl)(thien-2-yl)-methyl]amine are obtained in theform of an oil which crystallizes at 20° C. [a]20)=−31.7° (c=0.5% indichloromethane).

EXAMPLE 78

[0568] On carrying out the operation according to the procedure ofExample 1 starting with 3.4 g of1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]-azetidin-3-ol, 0.72cm³ of methanesulfonyl chloride and 3.8 g of 4-dimethylaminopyridine,1.9 g of 1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]-azetidine areobtained, after recrystallization from 40 cm³ of acetonitrile, in theform of crystals melting at 210° C. [[NMR spectrum in DMSO-d₆, T=300K, δin ppm (300 MHz): 1.15 (3H, t, J=6 Hz, CH₃), 2.92 (2H, q, J=6 Hz, CH₂),3.83 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.75 (1H, s, NCH), between 7.20and 7.50 (15H, m, 3 phenyls)].

[0569] 1-Benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olmay be obtained by carrying out the operation according to the proceduredescribed in Example 1 starting with 2.4 g of benzylethylsulfone, 2.2cm³ of diisopropylamine, 10 cm³ of 1.6 N n-butyllithium in solution inhexane, 65 cm³ of tetrahydrofuran and 3.1 g of1-benzhydrylazetidin-3-one. 3.6 g of1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol areobtained, after recrystallization from 30 cm³ of acetonitrile, in theform of white crystals melting at 222° C.

[0570] Benzylethylsulfone may be prepared by carrying out the operationaccording to the procedure of Example 2 starting with 6.3 g ofbenzylethylsulfide, 50 cm³ of acetic acid, 50 cm³ of water, 25 cm³ of 36N sulfuric acid and 24.8 g of oxone^(R). 3.2 g of benzylethylsulfone areobtained, by recrystallization from 20 cm³ of ethyl ether, in the formof a solid melting at 86° C.

[0571] Benzylethylsulfide may be prepared in the following manner: 1.2 gof sodium hydride are added in small portions to a solution of 5 g ofbenzylmercaptan in 50 cm³ of dimethylformamide under argon, and then3.36 cm³ of ethyl iodide are poured in, while the temperature ismaintained below 45° C. The mixture is stirred for 2 hours and thentaken up in 200 cm³ of ethyl ether. The organic phase is washed with 200cm³ of water and then with 3 times 100 cm³ of water, dried overmagnesium sulfate and concentrated to dryness under reduced pressure(2.7 kPa). 6.3 g of benzylethylsulfide are obtained in the form of apale yellow liquid.

EXAMPLE 79

[0572] 0.083 g of 1-amino-4-methylpiperazine is added to a solution of0.45 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]methylene]azetidinein 5 cm³ of dimethylformamide. The mixture is stirred for 20 hours atroom temperature and then 40 cm³ of ethyl acetate are added. The organicphase is washed with 4 times 20 cm³ of water, dried over magnesiumsulfate and concentrated to dryness under reduced pressure (2.7 kPa).The residue is triturated with 10 cm³ of ethyl ether, filtered and thendried. 0.2 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[(N-4-methylpiperazinylcarbamoyl)phenyl]methylene}azetidineis obtained in the form of a yellow solid melting at 162° C. [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 2.20 (3H, s, NCH₃),2.40 (4H, m, 2 NCH₂), 2.90 (4H, m, 2 NCH₂), 2.95 (3H, s, SCH₃), 3.80(2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s, NCH), 7.40 (4H, d, J=7Hz, 4CH arom.), 7.50 (4H, d, J=7 Hz, 4CH arom.), 7.55 (2H, m, 2CHarom.), 7.80 (2H, m, 2CH arom.), 9.50 (1H, s, CONH)].

[0573]1-[Bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)[3-(pentafluorophenoxycarbonyl)phenyl]-methylene]azetidinemay be prepared in the following manner: 0.94 g ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.89 gof pentafluorophenol are added to a solution of 2.9 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinein 25 cm³ of dimethylformamide. The mixture is stirred for 20 hours atroom temperature and then taken up in 50 cm³ of ethyl acetate. Theorganic phase is washed with 100 cm³ of water, 200 cm³ of a saturatedaqueous sodium bicarbonate solution and then with twice 50 cm³ ofdistilled water, dried over magnesium sulfate and concentrated todryness under reduced pressure (2.7 kpa). The residue is chromatographedon a silica column (particle size 0.04-0.006 mm, diameter 2 cm), elutingwith a mixture of dichloromethane and ethanol (99/1 by volume). 0.92 gof1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)-[3-(pentafluorophenoxycarbonyl)phenyl]methylene]-azetidineis obtained in the form of a white foam.1-[Bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene]azetidinemay be prepared in the following manner: a 36% solution of hydrochloricacid at a temperature of 50° C. is added to a solution of 3.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidinein 5 cm³ of acetic acid. The heating is continued for 48 hours and thenthe mixture is evaporated to dryness under reduced pressure (2.7 Kpa).The residue is taken up in 30 cm³ of ethanol and again evaporated todryness. The residue is triturated in 35 cm³ of ethyl ether. 3.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-carboxyphenyl)(methylsulfonyl)methylene)]-azetidineare obtained in the form of a beige solid.

[0574]1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidinemay be prepared according to the procedure of Example 4, starting with11 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,150 cm³ of dichloromethane, 2.54 cm³ of methanesulfonyl chloride and10.7 g of 4-dimethylamino-pyridine, at room temperature for 3 hours. Theresidue obtained is purified by chromatography on a silica gel column(particle size 0.04-0.06 mm, diameter 4.5 cm) and eluted withdichloromethane and then with a mixture of dichloromethane and ethanol(99.6/0.4 by volume). The fractions are evaporated to dryness underreduced pressure (2.7 Kpa). 3.8 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]-azetidineare obtained in the form of a white foam.1-[Bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be prepared in the following manner: a solution of 5 g of3-cyanobenzyl methyl sulfone in 500 cm³ of tetrahydrofuran is added over15 minutes to a solution of 17.6 cm³ of 1.6 M n-butyllithium in hexane,in 30 cm³ of tetrahydrofuran under argon, and cooled to −70° C. Themixture is stirred for 1 hour 30 minutes. Next, a solution of 7.8 g of1-[bis(4-chlorophenyl)methyl]-azetidin-3-one in 80 cm³ oftetrahydrofuran is poured in over 10 minutes. After stirring for 1 hour30 minutes, 60 cm³ of a saturated aqueous ammonium chloride solution arepoured in and then the mixture is allowed to return to room temperature.The mixture is taken up in 300 cm³ of ethyl acetate, the organic phasewashed with 200 cm³ of a saturated aqueous sodium chloride solution,dried over magnesium sulfate and evaporated under reduced pressure (2.7Kpa). 11 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methyl-(RS)]-azetidin-3-olare obtained in the form of a foam.

[0575] (3-Cyanobenzyl)methylsulfone may be prepared in the followingmanner: starting with a solution of 20.2 g of 3-chloromethylbenzonitrilein 200 cm³ of ethanol, 17.4 g of 85% sodium methanesulfinate are added.The mixture is stirred for 20 hours under reflux and then taken up in500 cm³ of ethyl acetate and 500 cm³ of water. The insoluble matter isfiltered off, the organic phase in the filtrate is dried over magnesiumsulfate and evaporated to dryness under reduced pressure (2.7 Kpa). Thesolid obtained is triturated with 100 cm³ of ethyl ether. Afterfiltration and drying of the solid, 21 g of (3-cyanobenzyl)methylsulfoneare obtained in the form of white crystals melting at 165° C.

[0576] 3-Chloromethylbenzonitrile may be prepared in the followingmanner: 32 g of 3-chloromethylbenzoamide in 200 cm³ of phosphorusoxychloride are heated at 95° C. for 3 hours, and then 1 liter of ice isloaded, the mixture stirred for 1 hour and extracted with 500 cm³ ofdichloromethane. The organic phase is washed with 200 cm³ of water,dried over magnesium sulfate and evaporated to dryness under reducedpressure (2.7 Kpa). 20.2 g of 3-chloromethylbenzonitrile are obtained inthe form of a white solid.

[0577] 3-Chloromethylbenzoamide may be prepared in the following manner:150 cm³ of a solution of ammonium hydroxide (d=0.90) are poured into asolution of 50 g of 3-chloromethylbenzoyl chloride in 150 cm³ of ethylether, the mixture is cooled, stirred for 1 hour, filtered and washedwith twice 200 cm³ of ethyl ether. 32 g of 3-chloromethylbenzoamide areobtained in the form of white crystals.

EXAMPLE 80

[0578] On carrying out the operation according to the procedure ofExample 79 starting with 0.5 g of1-[bis(4-chlorophenyl)methyl]-3-{(methylsulfonyl)-[3-(pentafluorophenoxycarbonyl)phenyl]methylene}-azetidine,0.06 cm³, 1,1-dimethylhydrazine and 5 cm³ of dimethylformamide, 0.125 gof1-[bis(4-chlorophenyl)methyl]-3-{(3-(2,2-dimethylcarbohydrazido)phenyl]-(methylsulfonyl)methylene}azetidineis obtained in the form of a white solid melting at 134° C. [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 2.60 (6H, s, N(CH₃)₂),2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80 (1H, s,NCH), 7.35 (4H, d, J=7 Hz, 4CH arom.), 7.45 (4H, d, J=7 Hz, 4CH arom.),7.50 (2H, m, 2CH arom.), 7.80 (2H, m, 2CH arom.), 9.50 (1H, s, CONH)].

EXAMPLE 81

[0579] On carrying out the operation according to the proceduredescribed in Example 1 starting with 2.2 g of1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.64 cm³ of methanesulfonyl chloride, 2.3 g of 4-dimethylaminopyridineand 75 cm³ of dichloromethane, 1.3 g of1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineare obtained, after purification by chromatography and crystallizationfrom diisopropyl ether, in the form of white crystals melting at 165° C.[NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 3.00 (3H, s,SCH₃), 3.92 (2H, s, NCH₂), 4.28 (2H, s, NCH₂), 5.40 (1H, s, NCH), 6.95(2H, dd, J=5 and 2 Hz, 2CH thio.), 7.15 (2H, d, J=2 Hz, 2CH thio.), 7.20(2H, m, 2CH arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.50 (2H, d, J=5 Hz,2CH thio.)].1-[Bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained according to the procedure described in Example 1,starting with 1.5 g of 1-[bis(thien-2-yl)methyl]azetidin-3-one, 4 cm³ of1.6 N n-butyllithium in hexane, 1.3 g of(3,5-dichlorobenzyl)methylsulfone and 40 cm³ of tetrahydrofuran. 2.2 gof1-[bis(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olare obtained, after purification by chromatography, in the form of whitecrystals melting at 145° C. 1-[Bis-thien-2-yl)methyl]azetidin-3-one maybe prepared by carrying out the operation as described in Example 73,starting with 4 g of 1-[bis(thien-2-yl)methyl]azetidin-3-ol, 2.6 cm³ ofdimethyl sulfoxide, 7.7 cm³ of triethylamine, 7.7 cm³ of oxalylchloride, and 100 cm³ of dichloromethane. The residue obtained ispurified by chromatography on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 30 cm) with, as eluent, a mixture ofcyclohexane/ethyl acetate (1/1 by volume). The fractions obtained areevaporated to dryness under reduced pressure (2.7 Kpa). 3.2 g of1-[bis(thien-2-yl)methyl]azetidin-3-one are obtained in the form ofcream-colored crystals melting at 70° C.1-[Bis(thien-2-yl)methyl]azetidin-3-ol may be prepared by carrying outthe operation as described in Example 73, starting with 6 g of1-[bis(thien-2-yl)methyl]amine, 2.5 cm³ of epibromohydrin, 2.6 g ofsodium bicarbonate and 50 cm³ of ethanol. 4 g of1-[bis(thien-2-yl)methyl]azetidin-3-ol are obtained in the form of beigecrystals melting at 115° C. 1-[Bis(thien-2-yl)methyl]amine may beprepared in the following manner: a solution of 5 cm³ ofthien-2-ylcarbonitrile in 50 cm³ of diethyl ether is poured dropwiseinto a suspension, cooled under argon to 10° C. , of thien-2-ylmagnesiumbromide (prepared from 1.29 g of magnesium and 3.22 cm³ 2-bromothiophenein 75 cm³ of diethyl ether). After refluxing for 1 hour and 30 minutes,the reaction medium is cooled to 5° C. and then 20 cm³ of methanol arepoured in dropwise, the suspension filtered and the solid washed withmethanol. The filtrate obtained a brown solution. 2.45 g of sodiumborohydride are added to this solution, under argon, in severalportions. The mixture is stirred at room temperature for 16 hours andthen diluted with ethyl acetate and supplemented with water slowly. Theorganic phase is extracted, washed with water, dried over magnesiumsulfate and evaporated to dryness under reduced pressure (2.7 kpa) at55° C. A brown oil is obtained which is chromatographed on a silica gelcolumn (particle size 0.2-0.063 mm, diameter 8 cm, height 25 cm) andeluted with a mixture of cyclohexane/ethyl acetate (90/10 and then 85/15by volume). Fractions 21 to 30 are combined and evaporated to drynessunder reduced pressure (2.7 kpa). 11 g of 1-[bis(thien-2-yl)methyl]amineare obtained in the form of a crystallized solid.

EXAMPLE 82

[0580] On carrying out the operation according to the proceduredescribed in Example 1 starting with 0.47 g of 4-dimethylaminopyridine,0.13 cm³ of methanesulfonyl chloride, 25 cm³ of dichloromethane and 0.48g of1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol,0.25 g of1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methylene]azetidine isobtained, after purification by chromatography and crystallization fromdiisopropyl ether, in the form of a white solid [NMR spectrum inDMSO-d₆, T=300K, δ in ppm (250 MHz): 2.23 (6H, s, 2 PhCH₃), 2.98 (3H, s,SCH₃), 3.76 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 5.55 (1H, s, NCH), 7.10(4H, d, J=7 Hz, 4 CH arom.), 7.32 (4H, d, J=7 Hz, 4 CH arom.), 7.43 (5H,s, phenyl)].1-(Bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olmay be prepared according to the procedure described in Example 39,starting with 0.59 g of bromo(bis-p-tolyl)methane, 20 cm³ ofacetonitrile, 0.3 g of potassium carbonate and 0.6 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol hydrochloride. Theresidue obtained is chromatographed on a silica gel column (particlesize 0.04-0.06 mm, diameter 4 cm, height 16 cm) with, as eluent, acyclohexane/ethyl acetate (7/3 by volume) mixture. The fractions areconcentrated to dryness under reduced pressure (2.7 Kpa). 0.48 g of1-(bis-p-tolylmethyl)-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olis obtained in the form of a white solid.

[0581] Bromo(di-p-tolyl)methane may be prepared according to theprocedure described by BACHMANN W. E., J. Am. Chem. Soc., 2135 (1933).

[0582] 3-[(Methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olhydrochloride may be prepared according to the procedure described inExample 39 starting with 7 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-ol,35 cm³ of dioxane, 35 cm³ of a 6.2 N solution of hydrochloric acid indioxane. 5 g of 3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-olhydrochloride are obtained in the form of a white solid.

[0583]3-[(Methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olmay be prepared according to the procedure described in Example 38(Method 1), starting with 10 g of1-benzhydryl-3-[(methylsulfonyl)(phenyl)methyl-(RS)]azetidin-3-ol, 600cm³ of dichloromethane and 2.52 cm³ of vinyl chloroformate. The residueis chromatographed on a silica gel column (particle size 0.06-0.2 mm,diameter 5.2 cm, height 36 cm³ with, as eluent, a cyclohexane/ethylacetate (7/3 by volume) mixture. The fractions are evaporated to drynessunder reduced pressure (2.7 Kpa). 7 g of3-[(methylsulfonyl)(phenyl)methyl-(RS)]-1-(vinyloxycarbonyl)azetidin-3-olare obtained in the form of a white solid.

EXAMPLE 83

[0584] A solution of 30 mg of sodium borohydride in 2 cm³ of methanol ispoured into a solution of 0.77 g of(−)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinein 20 cm³ of methanol at 0° C. under argon. After stirring for 4 hoursat 0° C., water is added and the mixture is then extracted withdichloromethane. The organic phase is washed with a saturated aqueoussodium chloride solution, dried over magnesium sulfate and thenevaporated to dryness under reduced pressure (2.7 kpa). The white foamobtained is purified on a silica gel column (particle size 0.04-0.06 mm,diameter 3.2 cm, height 17 cm) with, as eluent, a cyclohexane/ethylacetate (60/40 by volume) mixture. 0.1 g of(+)-1-[(4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained, after crystallization from 1.5 cm³ of absolute ethanol, inthe form of white crystals melting at 190° C., [a]²⁰ _(D=+)4.2° (c=0.5%in methanol) [NMR spectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 3.05(3H, s, SCH₃), 3.95 (2H, s, NCH₂), 4.22 (2H, s, NCH₂), 4.48 (2H, d, J=6Hz, CH₂O), 4.75 (1H, s, NCH), 5.15 (1H, t, J=6 Hz, OH), 7.20 (2H, m, 2CHarom.), 7.28 (2H, d, J=7 Hz, 2CH arom.), 7.40(5H, m, 5 CH arom.), 7.50(2H, d, J=7 Hz, 2CH arom.)].

[0585](−)-1-[(4-Chlorophenyl)(4-formylphenyl)-methyl]-3-[(3,5-difluorophenyl)methylsulfonyl-methylene]azetidinemay be prepared in the following manner: 3.32 cm³ of a 5 N solution ofhydrochloric acid are poured into a solution of 0.83 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidinein 5 cm³ of tetrahydrofuran and then the mixture is kept stirring for 20hours. Dichloromethane and water are added to the reaction mediumfollowed by a 30% aqueous solution of sodium hydroxide until a pH 14 isobtained. The aqueous phase is extracted with dichloromethane, theorganic phase is washed successively with water, with a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate,filtered and evaporated to dryness under reduced pressure (2.7 kpa). 0.8g of(−)-1-[(4-chlorophenyl)(4-formylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of a white foam.

[0586](+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidinemay be obtained in the following manner: 0.93 g of1,8-Diazabicyclo[5-4-01-undec-7-ene is poured dropwise into a solutionof 2.42 g of the mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluoro-phenyl)(methylsulfonyl)methyl-(R*)]azetidineand3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*))-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidinein 25 cm³ of tetrahydrofuran under argon at 0° C. After stirring for 1hour and 30 minutes at 0° C., the reaction medium is diluted with ethylacetate, washed with water and with a saturated aqueous sodium chloridesolution. The organic phase is dried over magnesium sulfate, filteredand evaporated to dryness under reduced pressure. The crude product ispurified on a silica gel column (particle size 0.04-0.06 mm, diameter4.8 cm, height 17.5 cm) with, as eluent, a cyclohexane/ethyl acetate(80/20 by volume) mixture. 1.21 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidineare obtained in the form of a yellow foam.

[0587] The mixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methyl-(R*)]azetidineand3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidinemay be prepared in the following manner: 3.27 cm³ of n-butyllithium arepoured dropwise into a solution of 1.08 g of 3-5-difluorobenzyl methylsulfone under argon, cooled to −70° C., and then the mixture is keptstirring for 1 hour at −70° C. and then a solution of 1.80 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-onein 10 cm³ of tetrahydrofuran is poured in dropwise. After stirring for 3hours at −70° C. and for 1 hour at −20° C. , a solution of 0.74 cm³ ofacetyl chloride in 10 cm³ of anhydrous diethyl ether at −20° C. ispoured in and the mixture is stirred for 2 hours at −20° C. The reactionmedium is thrown over water, the mixture is extracted with ethylacetate, the organic phase washed with water and with a saturatedaqueous sodium chloride solution, dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kpa). 2.42 g of themixture of the two diastereoisomers3-acetoxy-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(R*)]azetidineand3-acetoxy-1-{(4-chlorophenyl)-[4-(1,3-dioxolan-2-yl)phenyl]methyl-(R*)}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(S*)]azetidineare obtained in the form of a yellow oil.

[0588](+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-onemay be prepared in the following manner: 2.24 cm³ of triethylamine arepoured into a solution of 1.38 g of(+)-1-{(4-chloro-phenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-olin 20 cm³ of anhydrous dimethyl sulfoxide under argon, followed dropwiseby 1.65 g of a solution of sulfur trioxide pyridine complex in 20 cm³ ofanhydrous dimethyl sulfoxide. After stirring for 1 hour and 15 minutesat room temperature, the reaction medium is thrown over ice, extractedwith ethyl acetate, the organic phase washed with water, with asaturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kpa). The oily residue obtained (1.31 g), combined with anotherbatch of the same crude compound (1.21 g), are purified together on asilica gel column (particle size 0.04-0.06 mm, diameter 4.8 cm, height18 cm), with, as eluent, a cyclohexane/ethyl acetate (80/20 by volume)mixture. 1.87 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-oneare obtained in the form of a yellow oil. [a]²⁰365 nm=+5.9° (c=0.5;methanol).

[0589](+)-1-{(4-Chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-olmay be described according to the procedure described in Example 73,starting with 4.43 g of(+)-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine, 40 cm³of absolute ethanol, 1.25 cm³ of epibromohydrin and 1.28 g of sodiumbicarbonate. 1.66 g of(+)-1-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}azetidin-3-olare obtained in the form of a yellow oil.

[0590] Chiral(+)-{(4-chlorophenyl)[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine may beobtained in the following manner: 3.95 cm³ of ethylene glycol are pouredinto a suspension of 18.16 g of chiral(R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochloride, in1000 cm³ of toluene, and 0.82 g of para-toluenesulfonic acid monohydrateis added. After stirring for 20 hours at the reflux temperature, thereaction medium is cooled, washed with a saturated aqueous sodiumbicarbonate solution, with water and with a saturated aqueous sodiumchloride solution. The organic phase is dried over magnesium sulfate,filtered and concentrated to dryness under reduced pressure. The residueobtained is purified on a silica gel column (particle size 0.04-0.06 mm,diameter 8.4 cm, height 21.5 cm) with, as eluent, a cyclohexane/ethylacetate (30/70 by volume) mixture, collecting 250 cm³ fractions.Fractions 23 to 30 are concentrated to dryness under reduced pressure(2.7 kpa). 1.39 g of chiral(+)-{(4-chlorophenyl)-[4-(1,3-dioxolan-2-yl)phenyl]methyl}amine areobtained in the form of a yellow oil.

[0591] Chiral (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]aminehydrochloride may be prepared in the following manner: 330 cm³ ofmethanol are poured into a solution of 51.4 g of the diastereoisomerN-{(4-chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)}-(R)-2-phenylglycinolin 660 cm³ of anhydrous dichloromethane, the mixture cooled with an icebath, 60.96 g of lead tetraacetate added, the mixture stirred for 5minutes and then 1 liter of a phosphate buffer solution pH 7 poured in.After stirring for 30 minutes at room temperature, the mixture isfiltered and the aqueous phase is extracted with dichloromethane. Theorganic phase is concentrated to dryness under reduced pressure (2.7kpa). The residue is taken up in 1 liter of diethyl ether andsupplemented with 1 liter of a 3 N aqueous solution of hydrochloricacid, the mixture is stirred for 15 minutes at room temperature, theaqueous phase is separated, washed with ethyl acetate and thenconcentrated to dryness under reduced pressure (2.7 kpa). 18.16 g ofchiral (R*)-[(4-chlorophenyl)(4-formylphenyl)methyl]amine hydrochlorideare obtained in the form of a white solid.

[0592]N-{(4-chlorophenyl)[4-(diethoxymethyl)phenyl]methyl-(R*)}-(R)-2-phenylglycinolmay be prepared in the following manner: 286 cm³ of 1.6 M n-butyllithiumin hexane are poured dropwise into a solution, cooled to −70° C., underargon, of 87.7 g of 4-bromochlorobenzene and the mixture is stirred for15 minutes at −70° C. This solution obtained is then added dropwise tothe following solution cooled to 0° C. : 30 g of(R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglycinol in 300 cm³ ofdiethyl ether. The mixture is stirred for 2 hours at 0° C. and thenthrown over water. The organic phase is washed with water and then witha saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure(2.7 kpa). 71.5 g of a reddish oil are obtained, which oil is purifiedon a silica gel column (particle size 0.04-0.06 mm, diameter 11 cm,height 45 cm), with, as eluent, a cyclohexane/ethyl acetate (85/15 byvolume, then 80/20 and 75/25) mixture, collecting 1 liter fractions.Fractions 11 to 17 are concentrated to dryness under reduced pressure(2.7 kpa). 39.85 g of the sole diastereoisomerN-{(4-chlorophenyl)-[4-(diethoxymethyl)phenyl]methyl-(R*)}-(R)-2-phenylglycinolare obtained in the form of an orange red oil.

[0593] (R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglycinol may beprepared in the following manner: 35.9 cm³ of4-(diethoxymethyl)benzaldehyde are poured into a white suspension of24.7 g of (R)-(−)-2-phenylglycinol in 500 cm³ of toluene. The cloudyyellow solution is heated under reflux for 6 hours 30 minutes, and isthen stirred at room temperature for 20 hours. After concentrating thereaction medium to dryness under reduced pressure (2.7 kpa), 61.6 g of(R)-N-[4-(diethoxymethyl)benzylidene]-2-phenylglycinol are obtained inthe form of a yellow oil.

EXAMPLE 84

[0594] On carrying out the operation according to the procedure ofExample 1, but starting with 5.6 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol,100 cm³ of dichloromethane, 1.59 g of methanesulfonyl chloride and 4.5 gof 4-dimethylaminopyridine. The mixture is kept stirring for 3 hours atroom temperature. The crude product obtained is purified bychromatography on a silica gel column (particle size 0.04-0.06 mm,diameter 4 cm³ and weight of silica 250 g), eluting at a nitrogenpressure of 0.5 bar with an ethyl acetate/cyclohexane (30/70 by volume)mixture and collecting 100 cm³ fractions. Fractions 12 to 18 arecombined, concentrated to dryness under reduced pressure (2.7 kpa). 3.2g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)-methylene}azetidineare obtained in the form of a white foam [NMR spectrum in DMSO-d₆,T=300K, δ in ppm (300 MHz): 1.30 (9H, s, OC(CH₃)₃), 2.65 (3H, s, J=6 Hz,NCH₃), 2.85 (3H, s, SCH₃), 3.50 (2H, s, NCH₂), 3.90 (2H, s, NCH₂), 4.45(1H, s, NCH) between 6.85 and 7.05 (8H, m, 8 CH arom.), 7.10 (4H, d, J=7Hz, 4 CH arom.)].1-[Bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl]-(methylsulfonyl)methyl-(RS)}azetidin-3-olmay be prepared according to the procedure described in Example 1starting with 3.8 g of[3-(N-tertbutyloxy-carbonyl-N-methylamino)benzyl]methylsulfone, 50 cm³of tetrahydrofuran, 9.5 cm³ of a 1.6 N solution of n-butyllithium inhexane, 3.82 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one. The crudeproduct is purified by chromatography on a silica gel column (particlesize 0.04-0.06 mm, diameter 4 cm, weight of silica 250 g), eluting at anitrogen pressure of 0.5 bar with dichloromethane and then with adichloromethane and ethanol mixture (99/1 by volume) and collecting 500cm³ fractions. Fractions 10 to 16 are combined, concentrated to drynessunder reduced pressure (2.7 kPa). 5.6 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methyl-(RS)}azetidin-3-ol,are obtained in the form of a foam.

EXAMPLE 85

[0595] 2.7 g of1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidinein 30 cm³ of dioxane and 30 cm³ of a 4.7 N solution of hydrochloricdioxane are stirred for 20 hours. The reaction medium is evaporated todryness under reduced pressure (2.7 kpa), taken up in 50 cm³ of waterand 50 cm³ of ethyl acetate, stirred and neutralized carefully with asaturated aqueous sodium bicarbonate solution. The organic phase isseparated, dried over magnesium sulfate, treated with animal charcoaland then concentrated under reduced 3 pressure (2.7 kpa) to a volume ofabout 25 cm , then filtered, concentrated to dryness under reducedpressure. 1.3 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidineare obtained in the form of white crystals melting at 228° C. [NMRspectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 2.65 (3H, s, J=6 Hz,NCH₃), 2.95 (3H, s, SCH₃), 3.80 (2H, s, NCH₂), 4.20 (2H, s, NCH₂), 4.80(1H, s, NCH), 5.85 (1H, q, J=6 Hz, NH), 6.55 (3H, m, 3 CH arom.), 7.15(1H, t, J=7 Hz, CH arom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 7.50 (4H, m,4CH arom.)].

EXAMPLE 86

[0596] On carrying out the operation as in Example 1, starting with 0.40g of a mixture of two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,0.10 cm³ of methanesulfonyl chloride and 0.37 g of4-dimethylaminopyridine, 0.13 g of(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidineis obtained, after chromatography on a silica gel column (particle size0.06-0.200 mm, diameter 1.2 cm, height 20 cm), at an argon pressure of 1bar with a mixture of ethyl acetate and cyclohexane (40/60 by volume) aseluent and collecting 20 cm³ fractions, in the form of a pinkish solid[NMR spectrum in DMSO-d₆, T=300K, δ in ppm (300 MHz): 3.05 (3H, s,SCH₃), 4.05 (2H, s, NCH₂), 4.35 (2H, m, NCH₂), 5.25 (1H, s, NCH), 7.20(2H, d, J=8 Hz, 2CH arom.), 7.35 (1H, t, J=8 Hz, CH arom.), 7.45 (2H, d,J=7 Hz, 2CH arom.), 7.50 (2H, d, J=7 Hz, 2CH arom.), 7.70 (1H, d, J=2Hz, CH thiazole), 7.75 (1H, d, J=2 Hz, CH thiazole)].

[0597] The mixture of the two diastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olmay be obtained in the following manner: on carrying out the operationas in Example 72, starting with 1.01 g of(RS)-bromo(4-chlorophenyl)thiazol-2-ylmethane and 0.55 g of(RS)-3-[3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-olhydrochloride and after chromatography on a silica gel column (particlesize 0.06-0.200 mm, diameter 4.4 cm, height 38 cm), at an argon pressureof 0.5 bar and eluting with a mixture of ethyl acetate and cyclohexane(30/70 by volume and then 40/60 from fraction 16) and collecting 60 cm³fractions, fractions 21 to 35 are combined and concentrated to drynessunder reduced pressure (2.7 kPa). 0.40 g of the mixture of the twodiastereoisomers1-[(4-chlorophenyl)(thiazol-2-yl)methyl-(RS)]-3-[3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olwhich is obtained in the form of a whitish solid.

EXAMPLE 87

[0598] 50 mm³ of pyrrolidine are added to a solution of 0.32 g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, and 5 mg of sodium iodide in 10 cm³ of dichloromethane.After stirring for 20 hours at 20° C., 50 mm³ of pyrrolidine are addedto the mixture, stirred for 8 hours and then 50 mm³ of pyrrolidine areagain added and the mixture is stirred for 20 hours at 20° C. Thereaction mixture is washed with water and then the organic phase isdried over magnesium sulfate and concentrated to dryness under vacuum(2.7 kPa). The residue obtained is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), atan argon pressure of 0.1 bar, eluting with dichloromethane and then witha dichloromethane and methanol mixture (97.5/2.5 by volume) andcollecting 3 cm³ fractions. Fractions 12 to 40 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.18 g of1-{(R^(*))-(4-chlorophenyl)[4-pyrrolidinylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [a]²⁰365nm=-22.5°+/−0.7 (c=0.5%; dichloromethane) [H NMR spectrum (300 MHz,CDCl₃, 6 in ppm): 1.78 (mt, 4H), 2.51 (mt, 4H), 2.81 (s, 3H), 3.58 (s,2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].1-{(R)-[(4-chloromethyl)phenyl(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, may be prepared by carrying out the operation in thefollowing manner: 12.4 cm³ of methanesulfonyl chloride are added to asolution of 28.0 g of the mixture of the 2 diastereoisomers (forms A)1-{(R^(*))-[(4-chloromethyl)-phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-oland1-{(R)-[(4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-oland 32 g of 4-dimethylaminopyridine, in 500 cm³ of dichloromethane.After stirring for 1 hour at 10° C. and then 1 hour at 20° C. , thereaction mixture is washed with 500 cm³ of water, the organic phase isdried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). The residue is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 6 cm, height 30 cm), at anargon pressure of 0.2 bar, eluting with dichloromethane and collecting250 cm³ fractions. Fractions 9 to 25 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 6.3 g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, are obtained in the form of a white foam.

[0599] The mixture of the 2 diastereoisomers (forms A)1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and1-{(R)-[(4-chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,may be prepared by carrying out the operation in the following manner:60 mm³ of thionyl chloride are added to a solution of 0.20 g of themixture of the 2 diastereoisomers (forms A) 1-{(R^(*))-[4-(chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and 1-{(R)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol,in 10 cm³ of dichloromethane. After stirring for 20 hours at 20° C., 5cm³ of a saturated aqueous sodium hydrogen carbonate solution are addedto the reaction mixture and then the mixture is stirred for 15 minutes.The mixture is separated after settling out, the organic phase is washedwith water, dried over magnesium sulfate and then concentrated todryness under reduced pressure (2.7 kPa). The residue is chromatographedon a silica gel column (particle size 0.04-0.06 mm, diameter 1.0 cm,height 20 cm), at an argon pressure of 0.2 bar, eluting with acyclohexane and ethyl acetate mixture (75/25 by volume) and collecting20 cm³ fractions. Fractions 4 to 7 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 0.17 g of the mixture of the 2diastereoisomers (forms A)1-{(R)-[4-(chloromethyl)phenyl]-[4-chlorophenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and 1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-olis obtained in the form of a white foam.

[0600] The mixture of the 2 diastereoisomers (forms A)1-{(R)-4-(chlorophenyl)phenyl][4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and 1-{(R) -(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]zetidin-3-ol,may be prepared by carrying out the operation in the following manner:1.6 cm³ of a 1.5 M solution of diisobutylaluminum hydride in toluene areadded to a solution, maintained under argon and cooled to −30° C., of0.58 g of the mixture of the 2 diastereoisomers (forms A)3-acetoxy-1-{(R)— (4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidine and 3-acetoxy-1-{(R) -(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidine, in 10 cm³ of anhydrous toluene. Afterstirring for 15 minutes at −30° C., 1.0 cm³ of this same hydridesolution is again added and then the mixture is allowed to return to 0°C. After stirring for 30 minutes, the stirred mixture is supplementedwith 3 cm³ of water and 6 cm³ of 1 N sodium hydroxide and then extractedwith 25 cm³ of dichloromethane. The organic phase is washed with 5 cm³of water, 5 cm³ of brine, and then dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). The residue ischromatographed on a silica gel column (particle size 0.06-0.200 mm,diameter 1.2 cm, height 30 cm), at an argon pressure of 0.1 bar, elutingwith a cyclohexane and ethyl acetate mixture (50/50 by volume) andcollecting 30 cm³ fractions. Fractions 4 to 12 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.42 g of themixture of the 2 diastereoisomers (forms A) 1-{(R^(*))-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,and1-{(R^(*))-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)(3,5-difluorophenyl)(methylsulfonyl)methyl)]-azetidin-3-olis obtained in the form of a white lacquer.

[0601] The mixture of the 2 diastereomers (forms A)3-acetoxy-1-{(R^(*))-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)}azetidineand3-acetoxy-1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)}azetidinemay be prepared by carrying out the operation as described in Example40, starting with 1.0 g of (3,5-difluorobenzyl)methylsulfone, 30 cm³ oftetrahydrofuran, 3 cm³ of a 1.6 N solution of n-butyllithium in hexane,1.45 g of1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)-phenyl]methyl}azetidin-3-one,form A isomer, and 0.43 cm³ of acetyl chloride. 1.28 g of the mixture ofthe 2 diastereoisomers (forms A)3-acetoxy-1-{(R)-(4-chlorophenyl)[4-methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand 3-acetoxy-1-{(R^(*))-(4-chlorophenyl)[4-methoxy-carbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineare obtained in the form of a beige foam.

[0602] 1-{(R)-[(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, form A isomer, may beprepared by carrying out the operation as described in Example 40,starting with 0.55 cm³ of oxalyl chloride, 25 cm³ of dichloromethane,0.90 cm³ of dimethyl sulfoxide, 1.75 g of1-{(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, and2.70 Cm³ of triethylamine. 1.45 g of1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one,form A isomer, are obtained in the form of a yellow foam. 1-{(R)(4-chlorophenyl) [4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, form Aisomer, may be prepared by carrying out the operation according to theprocedure described by KATRITZKY A. R. et al., in J. Heterocycl. Chem.,(1994), 271 from 2.0 g of methyl(+)-4-[(R)-amino-(4-chlorophenyl)methyl]benzoate, 30 cm³ of ethanol,0.60 g of sodium hydrogen carbonate and 0.60 cm³ of epibromhydrin. 1.76g of1-{(R^(*))-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]-methyl}azetidin-3-ol,form A isomer, are obtained in the form of a pasty solid.

[0603] Methyl (+)-4-[(R)-amino-(4-chlorophenyl)methyl]benzoate may beprepared by carrying out the operation in the following manner: 2.51 gof D-(−)-tartaric acid are added to a solution of 9.2 g of methyl(4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate in 10 cm³ of methanol.The solution is concentrated to dryness under reduced pressure (2.7kPa). The cream-colored foam obtained is dissolved in 50 cm³ of ethanolcontaining 5% water and the resulting solution is allowed to crystallizefor 20 hours at 20° C. The crystals are filtered, washed with ethanolcontaining 5% water, drained and then dried under reduced pressure (2.7kPa). 3.4 g of white crystals are obtained which are called “A crystals”[and which are stored for the subsequent preparation of the secondenantiomer, methyl (−)-4-[(R)-amino-(4-chlorophenyl)methyl]benzoate].The mother liquors are concentrated to dryness and a white foam (8.1 g)is obtained which is dissolved in 100 cm³ of ethyl acetate. The solutionobtained is supplemented with 50 cm³ of 1 N sodium hydroxide, stirredand separated after settling out. The organic phase is washed with 50cm³ of water and then dried over magnesium sulfate and concentrated todryness under reduced pressure (2.7 kPa). A yellow solid is obtainedwhich is dissolved in 100 cm³ of methanol. The solution obtained issupplemented with 1.85 g of L-(+)-tartaric acid and the resultingsolution is concentrated to dryness under reduced pressure (2.7 kPa). Acream-colored foam is obtained which, once dissolved in 27 cm³ ofethanol containing 4% water, is allowed to crystallize for 20 hours at20° C. The crystals are filtered, washed with ethanol containing 4%water, drained and then dried under reduced pressure (2.7 kPa). 3.4 g ofmethyl (+)-4-[(R)-amino-(4-chlorophenyl)methyl]benzoate L-(+)-tartratecrystals are obtained which are recrystallized from 60 cm³ of ethanolcontaining 5% water. After draining and then drying, 2.78 g of whitecrystals are obtained which are dissolved in 50 cm³ of ethyl acetate.The solution obtained is supplemented with 100 cm³ of 1 N sodiumhydroxide, stirred and separated after settling out. The organic phaseis washed with 50 cm³ of water and then dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). 2.1 g ofmethyl (+)-4-[(R)-amino-(4-chlorophenyl)methyl]benzoate are obtained inthe form of a white solid.

[0604] Methyl 4-[(RS)-amino-(4-chlorophenyl)-methyl]benzoate may beprepared by carrying out the operation in the following manner: 3.9 cm³of hydrazine hydrate are added to a suspension of 16.3 g of methyl4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate in 200 cm³ ofmethanol. After stirring for 5 hours at the reflux temperature and thenfor 20 hours at 20° C., the reaction mixture is filtered and thefiltrate is concentrated to dryness under reduced pressure (2.7 kPa).The residue obtained is taken up in a mixture of 200 cm³ of water and200 cm³ of ethyl acetate. After stirring for 15 minutes, the resultingsuspension is filtered, the filtrate separated after settling out in aseparating funnel, and the organic phase is washed with 50 cm³ of water,dried over magnesium sulfate and concentrated to dryness under reducedpressure (2.7 kPa). 8.4 g of methyl4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate are obtained in the formof a pale yellow oil.

[0605] Methyl 4-[(RS)-phthalimido-(4-chlorophenyl)-methyl]benzoate maybe prepared by carrying out the operation in the following manner: 12.6g of potassium phthalimide are added to a solution of 11.6 g of methyl4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate in 70 cm³ ofdimethylformamide. After stirring for 3 hours at the reflux temperature,the reaction mixture is cooled to 20° C. and then supplemented with 300cm³ of ethyl acetate and 300 cm³ of water. After stirring, the mixtureis separated after settling out, the aqueous phase reextracted withtwice 100 cm³ of ethyl acetate, the combined organic phases are washedwith twice 400 cm³ of water and then dried over magnesium sulfate andconcentrated to dryness under reduced pressure (2.7 kPa). 16.3 g ofmethyl 4-[(RS)-phthalimido-(4-chlorophenyl)methyl]benzoate are obtainedin the form of a pasty yellow solid.

[0606] Methyl 4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate may beprepared by carrying out the operation in the following manner: 10.18 gof N,N′-carbonyldiimidazole and 54.3 cm³ of allyl bromide are added to asolution of 17.4 g of methyl4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate in 200 cm³ ofacetonitrile. After stirring for 30 minutes at 20° C., the reactionmixture is heated under reflux for 2 hours, stirred for 20 hours at 20°C. and concentrated to dryness under reduced pressure (2.7 kPa). Themixture, taken up in dichloromethane, is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm), at anargon pressure of 0.5 bar, eluting with dichloromethane and collecting500 cm³ fractions. Fractions 3 to 6 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 11.6 g of methyl4-[(RS)-bromo-(4-chlorophenyl)methyl]benzoate are obtained in the formof an oil which will be used as it is in the next step.

[0607] Methyl 4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate may beprepared by carrying out the operation in the following manner: 1.21 gof sodium borohydride are slowly added in small fractions to asuspension of 2.75 g of methyl 4-(4-chlorobenzoyl)benzoate in 200 cm³ ofmethanol at 20° C. (heating of the medium up to 50° C. occurs). Afterstirring for 20 hours at 20° C., the reaction mixture is concentrated toa reduced volume and then supplemented with 150 cm³ of dichloromethaneand, while stirring, with 100 cm³ of 0.5 N hydrochloric acid. Afterseparating after settling out, the organic phase is dried over magnesiumsulfate and concentrated to dryness under reduced pressure (2.7 kPa).2.5 g of methyl 4-[(RS)-(4-chlorophenyl)(hydroxy)methyl]benzoate areobtained in the form of a colorless oil which slowly crystallizes at 20°C., and which will be used as it is in the next step.

[0608] Methyl 4-(4-chlorobenzoyl)benzoate may be prepared by carryingout the operation in the following manner: 27.4 cm³ oftri-n-butylphosphine are added, under argon, to a solution, cooled to−22° C. , of 19.3 g of terephthalic acid chloride monomethyl ester in200 cm³ of tetrahydrofuran. After stirring for 20 minutes at −22° C., asolution of 4-chlorophenylmagnesium bromide (prepared from 19.15 g of4-bromochlorobenzene, 2.43 g of magnesium and an iodine crystal in 100cm³ of diethyl ether under reflux) is poured in while this temperatureis maintained. After stirring for 30 minutes at −22° C., 150 cm³ of 1 Nhydrochloric acid are slowly added, the mixture is allowed to return to20° C. and then the medium is diluted with 200 cm³ of diethyl ether. Thewhite suspension obtained is filtered, the solid is washed with twice 50cm³ of water and then with twice 50 cm³ of diethyl ether. 16.2 g ofmethyl 4-(4-chlorobenzoyl)benzoate are obtained, after draining and thendrying under reduced pressure (2.7 kPa), in the form of a white solidmelting at 170° C.

EXAMPLE 88

[0609] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.025 g of3,3-dimethylpiperidine. The crude product is chromatographed on a silicagel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and then eluting with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 8 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.040 g of 1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 0.94 (s, 6H), 1.21 (mt, 2H), from 1.50 to1.65 (mt, 2H), 1.99 (broad s, 2H), 2.27 (unresolved complex, 2H), 2.81(s, 3H), 3.36 (s, 2H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84(tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 89

[0610] The operation is carried out as described in Example 87, startingwith 0.05 g of methylsulfonyl methyl 1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.025 g of thiomorpholine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.038 g of1-{(R^(*))-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): from 2.60 to 2.75 (mt, 8H), 2.80 (s, 3H),3.44 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt,J=8.5 and 2.5 Hz, 1H), 6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 90

[0611] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.025 g ofN-cyclohexyl-N-ethylamine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and ethanol mixture (95/5) by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. 0.022 g of1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]-methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃ with addition of a few drops of CD₃COOD-d4, δ in ppm):from 1.15 to 1.25 (mt, 2H), 1.29 (t, J=7.5 Hz, 3H), from 1.45 to 1.65(mt, 4H), 1.88 (mt, 2H), 2.17 (mt, 2H), 2.81 (s, 3H), 3.05 (q, J=7.5 Hz,2H), 3.27 (mt, 1H), 3.95 (mt, 2H), 4.18 (s, 2H), 4.40 (mt, 2H), 4.66 (s,1H), 6.82 (tt, J=8.5 and 2.5 Hz, 1H), 7.00 (mt, 2H), from 7.20 to 7.40(mt, 4H), 7.41 (d, J=8 Hz, 2H), 7.53 (d, J=8 Hz, 2H)

EXAMPLE 91

[0612] The procedure is carried out as described in Example 87, startingwith 0.05 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.032 g of4-(ethoxycarbonyl)piperazine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 8 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.021 g of1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonylpiperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl_(3 δ in ppm):) 1.25 (t, J=7 Hz, 3H), 2.36 (mt, 4H), 2.80(s, 3H), 3-44 (s, 2H), 3.46 (mt, 4H), 3.85 (mt, 2H), 4.13(q, J=7 Hz,2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98(mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 92

[0613] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.023 g ofN-cyclopropyl-N-propylamine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 9 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.026 g of1-{(R)-(4-chlorophenyl)[(4-N-cyclopropyl-N-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃ with addition of a few drops of CD₃COOD-d4, δ in ppm):0.34 (mt, 2H), 0.70 (mt, 2H), 0.91 (t, J=7 Hz, 3H), 1.08 (mt, 1H), 1.76(mt, 2H), 2.82 (s, 3H), 2.92 (d, J=7 Hz, 2H), 3.00 (mt, 2H), 3.90 (mt,2H), 4.25 (s, 2H), 4.37 (mt, 2H), 4.59 (s, 1H), 6.83 (tt, J=9 and 2.5Hz, 1H), 7.00 (mt, 2H), from 7.20 to 7.45 (mt, 8H)].

EXAMPLE 93

[0614] The operation is carried out as described in Example 87, but bystirring the reaction mixture for 6 days at 20° C., starting with 0.05 gof1-{(R)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, 5 mg of sodium iodide and0.020 g of diisopropylamine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 8 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.028 g of1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,form A isomer, is obtained in the form of a white foam [H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 1.00 (unresolved complex, 12H), 2.80 (s,3H), from 2.90 to 3.10 (unresolved complex, 2H), 3.58 (mt, 2H), 3.84(mt, 2H), 4.33 (mt, 2H), 4.48 (s, 1H), 6.82 (tt, J=8.5 and 2.5 Hz, 1H),6.97 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 94

[0615] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.027 g ofbis(2-methoxyethyl)amine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 10 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.014 g of1-{{(R)-(4-chlorophenyl){4-[bis(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,form A isomer, is obtained in the form of a white foam [H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 2.70 (broad t, J=5.5 Hz, 4H), 2.81 (s, 3H),3.29 (s, 6H), 3.46 (broad t, J=5.5 Hz, 4H) 3.65 (broad s, 2H), 3.85 (mt,2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98(mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 95

[0616] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.020 g ofdi-n-propylamine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 2.5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 8 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.025 g of 1-{(R)-(4-(chlorophenyl)[4-(di-n-propylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, δ in ppm): 0.85 (t, J=7 Hz, 6H) 1.45 (mt, 4H), 2.34 (t,J=7.5 Hz, 4H), 2.80 (s, 3H), 3.48 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H),4.50 (s, 1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to7.40 (mt, 8H)].

EXAMPLE 96

[0617] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.017 g of piperidine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 5 to 10 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.035 g of1-{(R^(*))-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): from 1.35 to 1.65 (mt, 6H), 2.35 (unresolvedcomplex, 4H), 2.80 (s, 3H), 3.41 (broad s, 2H), 3.84 (mt, 2H), 4.33 (mt,2H), 4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from7.20 to 7.40 (mt, 8H)].

EXAMPLE 97

[0618] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.020 g ofN-methylpiperazine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 2.5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 9 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.025 g of 1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 2.28 (s, 3H), from 2.30 to 2.60 (unresolvedcomplex, 8H), 2.80 (s, 3H), 3.45 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H),4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20to 7.40 (mt, 8H)].

EXAMPLE 98

[0619] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.018 g of morpholine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.022 g of1-{(R^(*))-(4-chlorophenyl)[4-(morpholin-4-ylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 2.41 (t, J=5 Hz, 4H), 2.80 (s, 3H), 3.43 (s,2H), 3.69 (t, J=5 Hz, 4H), 3.85 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H),6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt,8H)].

EXAMPLE 99

[0620] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.020 cm³ of D-prolinol.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.025 g of1-{(R^(*))-(4-chlorophenyl)[4-((2R)-hydroxymethylpyrrolidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, (CD₃)₂SO-d6 with addition of a few drops of CD₃COOD-d4, δ inppm): from 1.60 to 2.15 (mt, 4H), from 2.90 to 3.05 (mt, 1H), 2.98 (s,3H), 3.13 (mt, 1H), 3.38 (mt, 1H), from 3.50 to 3.60 (mt, 1H), 3.56 (d,J=5 Hz, 2H), 3.90 (mt, 2H), 4.04 (d, J=13.5 Hz, 2H), 4.21 (mt, 2H), 4.40(d, J=13.5 Hz, 2H), 4.78 (s, 1H), 7.14 (mt, 2H), 7.27 (tt, J=9 and 2.5Hz, 1H), from 7.30 to 7.55 (mt, 8H)].

EXAMPLE 100

[0621] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.015 g of diethylamine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 Cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 4 to 9 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.025 g of 1-{(R)—(4-chlorophenyl)[4-(diethylaminomethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, 1 in ppm): 1.03 (t, J=7 Hz, 6H), 2.50 (q, J=7 Hz, 4H),2.81 (s, 3H), 3.50 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.49 (s, 1H),6.84 (tt, J=9 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt,8H)].

EXAMPLE 101

[0622] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.026 g ofN-(hydroxyethyl)piperazine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height 8cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 10 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.032 g of1-{{(R^(*))-(4-chlorophenyl){4-[4-(hydroxyethyl)piperazin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): from 2.40 to 2.60 (mt, 8H), 2.54 (t, J=5.5Hz, 2H), 2.80 (s, 3H), 3.44 (s, 2H), 3.60 (t, J=5.5 Hz, 2H), 3.84 (mt,2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98(mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 102

[0623] The operation is carried out as described in Example 87 but bystirring the reaction mixture for 4 days at 20° C., starting with 0.05 gof1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.023 g of2(RS),6(RS)-dimethylpiperidine. The crude product is chromatographed ona silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height8 cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 9 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.024 g of 1-{(R)-(4-chlorophenyl)[4-(2(RS),6(RS)dimethyl(piperidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃ with addition of a few drops of CD₃COOD-d4, at atemperature of 353K, δ in ppm): from 1.20 to 1.45 (mt, 2H), 1.60(d, J=7Hz, 6H), from 1.80 to 2.10 (mt, 4H), 2.80 (s, 3H), 3.17 (mt, 2H), 3.90(mt, 2H), 4.34 (broad d, J=16 Hz, 1H), 4.40 (mt, 2H), 4.43 (broad d,J=16 Hz, 1H), 4.62 (s, 1H), 6.82 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt,2H), from 7.20 to 7.50 (mt, 8H)].

EXAMPLE 103

[0624] The operation is carried out as described in Example 87, but bystirring the reaction mixture for 4 days at 20° C., starting with 0.05 gof1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane, and 0.024 g ofpiperazin-2-one. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 8 cm),eluting with 80 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 2.5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 8 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.022 g of-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, δ in ppm) 2.62 (t, J=5.5 Hz, 2H), 2.80 (s, 3H), 3.11(s, 2H), 3.34 (mt, 2H), 3.51 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.51(s, 1H), 5.76 (unresolved complex, 1H), 6.84 (broad t, JHF=9 Hz, 1H),6.98 (mt, 2H) from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 104

[0625] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloro-methyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.020 g of L-prolinol. Thecrude product is chromatographed on a silica gel column (particle size0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm fractions immediately after usingthis eluent mixture. Fractions 3 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.028 g of1-{{(R)-(4-chlorophenyl){4-[(2S)-(hydroxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): from 1.50 to 2.00 (mt, 4H), 2.24 (mt, 1H),2.71 (mt, 1H), 2.80 (s, 3H), 2.93 (mt, 1H), 3.28 (d, J=13.5 Hz, 1H),3.45 (mt, 1H), 3.65 (d, J=11 and 4 Hz, 1H), 3.84 (mt, 2H), 3.91 (d,J=13.5 Hz, 1H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=8.5 and 2.5 Hz,1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 105

[0626] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.023 g of(2S)-(methoxymethyl)pyrrolidine. The crude product is chromatographed ona silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height8 cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 2to 6 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.037 g of1-{{(R)-(4-chlorophenyl){4-[(2S)-(methoxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 1.66 (mt, 2H), 1.90 (mt, 1H), 2.16 (mt, 1H),2.68 (mt, 1H), 2.80 (s, 3H), 2.89 (mt, 1H), from 3.25 to 3.45 (mt, 4H),3.31 (s, 3H), 3.84 (mt, 2H), 4.04 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H),4.50 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H) from 7.20to 7.40 (mt, 8H)].

EXAMPLE 106

[0627] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.020 g of2(RS),5(RS)-dimethylpyrrolidine. The crude product is chromatographed ona silica gel column (particle size 0.06-0.200 mm, diameter 8 mm, height8 cm), eluting with 80 cm³ of dichloromethane and then with adichloromethane and methanol mixture (95/5 by volume), collecting 2.5cm³ fractions immediately after using this eluent mixture. Fractions 3to 6 are combined and then concentrated to dryness under reducedpressure (2.7 kPa). 0.024 g of1-{(R)-(4-chlorophenyl)[4-(2(RS),5(RS)-dimethylpyrrolidin-1-ylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,mixture of isomers, form A, is obtained in the form of a white foam [¹HNMR spectrum (400 MHz, CDCl₃ with addition of a few drops of CD₃COOD-d4,δ in ppm): 1.68 (d, J=7 Hz, 6H), from 2.00 to 2.15 (mt, 4H), 2.82 (s,3H), 3.22 (mt, 2H), 3.92 (mt, 2H), 4.30 (s, 2H), 4.33 (mt, 1H), 4.45 (d,J=16.5 and 3 Hz, 1H), 4.63 (s, 1H), 6.84 (tt, J=8.5 and 2.5 Hz, 1H),7.00 (mt, 2H), from 7.20 to 7.55 (mt, 8H)].

EXAMPLE 107

[0628] The operation is carried out as described in Example 87, startingwith 0.05 g of1-{(R)-[4-(chloromethyl)phenyl]-4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.023 g of L-prolinamide.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 5 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.028 g of1-{(R)-(4-chlorophenyl)[4-((2S)-carbamoylpyrrolidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam [¹H NMR spectrum(400 MHz, CDCl₃, δ in ppm): from 1.65 to 1.85 (mt, 2H), 1.92 (mt, 1H),from 2.15 to 2.35 (mt, 2H), 2.80 (s, 3H), 3.00 (mt, 1H), 3.16 (dd, J=10and 5.5 Hz, 1H), 3.41 (d, J=13.5 Hz, 1H), 3.86 (mt, 2H), 3.89 (d, J=13.5Hz, 1H), 4.33 (mt, 2H), 4.51 (s, 1H), 5.23 (unresolved complex, 1H),6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), 7.17 (unresolved complex,1H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 108

[0629] The operation is carried out as described in Example 87, but bystirring the reaction mixture for 4 days at 20° C., starting with 0.05 gof1-{(R)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, 1.0 cm³ of dichloromethane and 0.021 g of diethanolamine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 8 cm), eluting with 80 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 2.5 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 9 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.004 g of1-{(R^(*))-(4-chlorophenyl)[4-(dihydroxyethylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,form A isomer, is obtained in the form of a white foam [H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 2.69 (t, J=5.5 Hz, 4H), 2.80 (s, 3H), 3.61(t, J=5.5 Hz, 4H), 3.65 (s, 2H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s,1H), 6.83 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40(mt, 8H)].

EXAMPLE 109

[0630] 0.055 g of imidazole is added to solution of 0.24 g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, in 5 cm³ of dichloromethane. After heating for 3 hoursunder reflux, the mixture is supplemented with 5 mg of sodium iodide.After stirring for 20 hours under reflux, the reaction mixture is cooledto 20° C. and then chromatographed on a silica gel column (particle size0.06-0.200 mm, diameter 1.0 cm, height 20 cm), eluting with 120 cm³ ofdichloromethane without fractionating, and then with a dichloromethaneand methanol mixture (98/2 and then 96/4 by volume), collecting 4 cm³fractions. Fractions 12 to 14 are combined and then concentrated todryness under reduced pressure (2.7 kPa). 0.039 g of1-{(R)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form A isomer, is obtained in the form of a white foam.

EXAMPLE 110

[0631] The operation is carried out as described in Example 87, startingwith 0.50 g of1-{(R)-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, 5 mg of sodium iodide, 15 cm³ of dichloromethane and0.0190 g of pyrrolidine. The crude product is chromatographed on asilica gel column (particle size 0.06-0.200 mm, diameter 1.5 cm, height20 cm), at an argon pressure of 0.1 bar, eluting with dichloromethaneand then with a dichloromethane and methanol mixture (95/5 by volume)and collecting 25 cm³ fractions. Fractions 20 to 40 are combined andthen concentrated to dryness under reduced pressure (2.7 kPa). 0.028 gof 1-{(R)-(4-chlorophenyl)[4-(pyrrolidin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white foam. [a]²⁰365nm+26.8°+/−0.8 (c=0.5%, dichloromethane) [H NMR spectrum (300 MHz,CDCl₃, δ in ppm): 1.78 (mt, 4H), 2.50 (mt, 4H), 2.80 (s, 3H), 3.57 (s,2H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=9 and 2.5Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].1-{(R^(*))-[4-(chloromethyl)phenyl](4-(chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, may be prepared by carrying out the operation asdescribed in Example 87, starting with 7.3 g of the mixture of the 2diastereoisomers (B forms)1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidin-3-oland 1-{(R^(*)) -[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-ol,8.2 g of 4-dimethylaminopyridine, 150 cm³ of dichloromethane and 3.2 cm³of methanesulfonyl chloride. The crude product is chromatographed on asilica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30cm), at an argon pressure of 0.2 bar, eluting with dichloromethane andcollecting 100 cm³ fractions. Fractions 15 to 30 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 2.50 g of1-{(R)-[4-(chloromethyl)phenyl]-(4-chlorophenyl)methyl}-3-{(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, are obtained in the form of a white foam.

[0632] The mixture of the 2 diastereoisomers1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland 1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,may be prepared by carrying out the operation as described in Example87, starting with 11.0 g of a mixture of the 2 diastereoisomers1-{(R)-[4-chlorophenyl)[4-(hydroxymethyl)phenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]-azetidin-3-oland -{(R)-[4-(chlorophenyl(4-(hydroxymethyl)phenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-ol,250 cm³ of dichloromethane and 3.1 cm³ of thionyl chloride. The crudeproduct is chromatographed on a silica gel column (particle size0.04-0.06 mm, diameter 3 cm, height 30 cm), at an argon pressure of 0.2bar, eluting with a cyclohexane and ethyl acetate mixture (70/30 byvolume) and collecting 50 cm³ fractions. Fractions 9 to 25 are combinedand then concentrated to dryness under reduced pressure (2.7 kPa). 7.3 gof the mixture of the 2 diastereoisomers (B forms)1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland 1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-olare obtained in the form of a white foam.

[0633] The mixture of the 2 diastereoisomers (B forms)1-{(R^(*))-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-oland1-{(R)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidin-3-olmay be prepared by carrying out the operation as described in Example87, starting with 18.0 g of the mixture of the 2 diastereoisomers (Bform)3-acetoxy-1-{(R^(*))-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidineand3-acetoxy-1-{(R^(*))-(4-chlorophenyl)[4-(methyloxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]-azetidine,150 cm³ of anhydrous toluene and 100 cm³ of a 20% solution ofdiisobutylaluminum hydride in toluene. The crude product ischromatographed on a silica gel column (particle size 0.06-0.200 mm,diameter 3 cm, height 30 cm), at an argon pressure of 0.1 bar, elutingwith a cyclohexane and ethyl acetate mixture (50/50 by volume) andcollecting 50 cm³ fractions. Fractions 15 to 30 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 11.0 g of themixture of the 2 diastereoisomers (B forms)1-{(R^()*)-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-oland 1-{(R^(*))-(4-chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl]azetidin-3-olare obtained in the form of white foam.

[0634] The mixture of the 2 diastereoisomers (B forms)3-acetoxy-1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand 3-acetoxy-1-{(R^(*)) -(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidinemay be prepared by carrying out the operation as described in Example40, starting with 11.2 g of (3,5-difluorobenzyl)methylsulfone, 350 cm³of tetrahydrofuran, 34 Cm³ of a 1.6 N solution of n-butyllithium inhexane, 11.2 g of 1-{(R^(*))-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, form B isomer, and 5.5cm³ of acetyl chloride. The crude product is chromatographed on a silicagel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm),eluting with a cyclohexane and ethyl acetate mixture (70/30 by volume)and collecting 100 cm³ fractions. Fractions 10 to 30 are combined andthen concentrated to dryness under reduced pressure (2.7 kPa). 21 g of astill impure cream-colored foam are obtained, which foam ischromatographed on a silica gel column (particle size 0.06-0.200 mm,diameter 4 cm, height 40 cm), eluting with dichloromethane andcollecting 100 cm³ fractions. Fractions 11 to 30 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 20.0 g of themixture of the 2 diastereoisomers (B forms)3-acetoxy-{(R^(*))-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(R)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]azetidineand3-acetoxy-{(R^(*))-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}-3-[(S)-(3,5-difluorophenyl)(methylsulfonyl)methyl)]-azetidineare obtained in the form of a white foam. 1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one, form B isomer, may beprepared by carrying out the operation as described in Example 40,starting with 8.7 cm³ of oxalyl chloride, 350 cm³ of dichloromethane,14.2 cm³ of dimethyl sulfoxide, 29.0 g of1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ole,form B isomer, and 43 cm³ of triethylamine. The crude product ischromatographed on a silica gel column (particle size 0.06-0.200 mm,diameter 4 cm, height 40 cm), eluting with dichloromethane andcollecting 250 Cm³ fractions. Fractions 7 to 25 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 15.5 g of1-{(R^(*))-(4-[chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-one,form B isomer, are obtained in the form of an orange-colored oil.

[0635] 1-{(R^(*))-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, form B isomer, may beprepared according to the procedure described by KATRITZKY A. R. et al.,in J. Heterocycl. Chem., (1994), 271, starting with 25.5 g of methyl(−)-4-[1-(R)-amino-1-(4-chlorophenyl)methyl]benzoate, 250 cm³ ofethanol, 7.9 g of sodium hydrogen carbonate, and 7.7 Cm³ ofepibromohydrin. 29 g of 1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]methyl}azetidin-3-ol, form B isomer, areobtained in the form of a yellow oil.

[0636] Methyl (−)-4-[(R)amino(4-chlorophenyl)methyl]benzoate, may beprepared by carrying out two successive recrystallizations of the whitecrystals (3.4 g) called “A crystals” of Example 87, from 68 cm³ ofethanol containing 5% water under reflux. The crystals obtained arefiltered, drained and then dried under reduced pressure (2.7 kPa). 2.2 gof methyl (−)-4-[(R^(*))amino(4-chlorophenyl)methyl]benzoateD-(−)-tartrate are obtained in the form of white crystals which aredissolved in 50 cm³ of ethyl acetate. The solution obtained issupplemented with 50 cm³ of 1 N sodium hydroxide, stirred and thenseparated after settling out. The organic phase is washed with 50 cm³ ofwater and then dried over magnesium sulfate and concentrated to drynessunder reduced pressure (2.7 kPa). 1.9 g of methyl(−)-4-[(R^(*))amino(4-chlorophenyl)methyl]benzoate are obtained in theform of a white solid [a]20° C. , 365 nm -58.1°+/−1 (c=0.5%)

EXAMPLE 111

[0637] The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ ofN-methylpiperazine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm),eluting with 50 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 3 cm³ fractionsimmediately after using this eluent mixture. Fractions 4 to 10 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.025 g of1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, is obtained in the form of a cream-colored foam [¹H NMRspectrum (300 MHz, CDCl₃, 6 in ppm): 2.28 (s, 3H), 2.44 (unresolvedcomplex, 8H), 2.80 (s, 3H), 3.45 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H),4.50 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to7.40 (mt, 8H)].

EXAMPLE 112

[0638] The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ of L-Prolinol.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 3 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 8 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.025 g of1-{{(R^(*))-(4-chlorophenyl){4-[(2S)-(hydroxymethyl)-pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a cream-colored foam [¹H NMRspectrum (300 MHz, CDCl₃, δ in ppm): from 1.80 to 2.00 (mt, 4H), 2.24(mt, 1H), 2.72 (mt, 1H), 2.80 (s, 3H), 2.94 (mt, 1H), 3.28 (d, J=13.5Hz, 1H), 3.45 (mt, 1H), 3.65 (d, J=10.5 and 3.5 Hz, 1H), 3.85 (mt, 2H),3.92 (d, J=13.5 Hz, 1H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt, J=8.5and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)].

EXAMPLE 113

[0639] The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R^(*))[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ of D-Prolinol.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 3 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 9 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.029 g of1-{{(R^(*))-(4-chlorophenyl){4-(2R)-(hydroxymethyl)pyrrolidin-1-ylmethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a cream-colored foam [¹H NMRspectrum (300 MHz, CDCl₃,δ in ppm): from 1.50 to 2.00 (mt, 4H), 2.24(mt, 1H), 2.71 (mt, 1H), 2.81 (s, 3H), 2.93 (mt, 1H), 3.28 (d, J=13.5Hz, 1H), 3.44 (split t, J=10.5 and 2.5 Hz, 1H), 3.66 (dd, J=10.5 and 3.5Hz, 1H), 3.85 (mt, 2H), 3.92 (d, J=13.5 Hz, 1H), 4.33 (mt, 2H), 4.50 (s,1H), 6.84 (tt, J=9 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40(mt, 8H)].

EXAMPLE 114

[0640] The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ of morpholine.The crude product is chromatographed on a silica gel column (particlesize 0.06-0.200 mm, diameter 8 mm, height 5 cm), eluting with 50 cm³ ofdichloromethane and then with a dichloromethane and methanol mixture(95/5 by volume), collecting 3 cm³ fractions immediately after usingthis eluent mixture. Fractions 2 to 9 are combined and then concentratedto dryness under reduced pressure (2.7 kPa). 0.047 g of1-{(R^(*))-(4-chlorophenyl)[4-(morpholin-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white foam [H NMR spectrum(300 MHz, CDCl₃, δ in ppm): 2.40 (mt, 4H), 2.81 (s, 3H), 3.43 (s, 2H),3.69 (mt, 4H), 3.84 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt,J=8.5 and 2.5 Hz, 1H), 6.99 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

EXAMPLE 115

[0641] The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with 0.05g of 1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 1.0 cm³ of dichloromethane and 0.030 cm³ ofthiomorpholine. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 8 mm, height 5 cm),eluting with 50 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 3 cm³ fractionsimmediately after using this eluent mixture. Fractions 2 to 9 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.047 g of1-{(R^(*))-(4-(chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white foam [¹H NMR spectrum(300 MHz, CDCl₃, δ in ppm): from 2.60 to 2.75 (mt, 8H), 2.81 (s, 3H),3.44 (s, 2H), 3.85 (mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (tt,J=8.5 and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.15 to 7.40 (mt, 8H)].

EXAMPLE 116

[0642] The operation is carried out as described in Example 110, but bystirring the reaction mixture for 48 hours at 20° C., starting with0.200 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 5.0 cm³ of dichloromethane and 0.120 cm³ ofpiperazin-2-one. The crude product is chromatographed on a silica gelcolumn (particle size 0.06-0.200 mm, diameter 1.0 cm, height 10 cm),eluting with 50 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 5 cm³ fractionsimmediately after using this eluent mixture. Fractions 3 to 13 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.090 g of1-{(R^(*))-(4-(chlorophenyl)[4-(piperazin-2-on-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white powder.

EXAMPLE 117

[0643] The operation is carried out as described in Example 110 startingwith 0.200 g of1-{(R^(*))-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 5.0 cm³ of dichloromethane and 0.120 of3,3-dimethylpiperidine. The crude product is chromatographed on a silicagel column (particle size 0.06-0.200 mm, diameter 1.0 cm, height 10 cm),eluting 3 with 50 cm³ of dichloromethane and then with a dichloromethaneand methanol mixture (95/5 by volume), collecting 5 cm³ fractionsimmediately after using this eluent mixture. Fractions 4 to 11 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 0.120 g of1-{(R^(*))-(4-chlorophenyl)[4-(3,3-dimethylpiperidinylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,form B isomer, is obtained in the form of a white powder.

EXAMPLE 118

[0644] The operation is carried out as described in Example 110, bystirring for 72 hours at 20° C., starting with 0.200 g of1-{(R)-[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene)]azetidine,form B isomer, 5.0 cm³ of dichloromethane and 0.080 of imidazole. Thereaction mixture is directly chromatographed on a silica gel column(particle size 0.06-0.200 mm, diameter 1.0 cm, height 10 cm), elutingwith 100 cm³ of dichloromethane without fractionating, and then with adichloromethane and methanol mixture (98/2 and then 96/4 by volume),collecting 5 cm³ fractions. Fractions 5 to 12 are combined and thenconcentrated to dryness under reduced pressure (2.7 kPa). 0.35 g of1-{(R)-(4-chlorophenyl)[4-(imidazol-1-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]}-azetidine,form B isomer, is obtained in the form of a white powder. [a]²⁰_(D=−)6.7° (c=0.5% dichloromethane)

EXAMPLE 119

[0645] 2.47 g of potassium tert-butoxide are added to a suspension of6.12 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.15 g ofmethyl 5-(methylsulfonylmethyl)thiophene-2-carboxylate in 200 cm³ oftetrahydrofuran, under an argon atomosphere, cooled to −70° C. Themixture is stirred for 1 hour 30 min at a temperature close to −70° C.,and then 1.7 cm³ of methanesulfonyl chloride in solution in 8 cm³ ofethyl ether is added. After stirring for 1 hour at a temperature closeto −70° C., the mixture is allowed to return to room temperature andthen 80 cm³ of distilled water are added. The mixture is concentrated ina rotary evaporator to one third of its initial volume, and is thenextracted with 500 cm³ of dichloromethane. The organic phase is washedwith three times 80 cm³ of distilled water, dried over magnesium sulfateand concentrated to dryness under reduced pressure (2.7 kPa). Theresidue obtained is chromatographed on a silica gel column (particlesize 0.02-0.04 mm, diameter 7.5 cm, height 35 cm), eluting at a nitrogenpressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30by volume) and collecting 40 cm³ fractions. Fractions 19 to 29 arecombined and then concentrated to dryness under reduced pressure (2.7kPa). 1.6 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine are obtained in the form of a cream-colored foam [¹H NMRspectrum (400 MHz, CDCl₃, δ in ppm): 2.91 (s, 3H), 3.88 (s, 3H), 4.08(mt, 2H), 4.37 (mt, 2H), 4.53 (s, 1H), from 7.25 to 7.45 (mt, 9H), 7.71(d, J=3.5 Hz, 1H)].

[0646] Fractions 34 to 48 are combined and then concentrated to drynessunder reduced pressure (2.7 kPa). 2.6 g of(RS)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine are obtained in the formof cream-colored powder [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, 6 inppm): 2.87 (s, 3H), 2.89 (d, J=8 Hz, 1H), 2.96 (d, J=8 Hz, 1H), 3.21 (d,J=8 Hz, 1H), 3.76 (d, J=8 Hz, 1H), 3.82 (s, 3H), 4.55 (s, 1H), 4.86 (s,1H), 6.86 (s, 1H), from 7.35 to 7.45 (mt, 9H), 7.73 (d, J=4 Hz, 1H)].

[0647] Methyl 5-(methylsulfonylmethyl) thiophene-2-carboxylate may beprepared in the following manner: 6.94 g of sodium methanesulfinate areadded, at room temperature, to a solution of 16 g of methyl5-bromomethylthiophene-2-carboxylate in 150 cm³ of tetrahydrofuran. Thesuspension is stirred for 2 hours 30 min under reflux, and then afteraddition of 50 cm³ of ethanol is again stirred for 3 hours under reflux.The mixture is concentrated to dryness under reduced pressure (2.7 kPa)and the residue obtained is supplemented with 150 cm³ of distilled waterand is then extracted with twice 300 cm³ of ethyl acetate. The organicphase is successively washed with 100 cm³ of distilled water and twice50 cm³ of saturated aqueous sodium chloride solution and then dried overmagnesium sulfate and concentrated to dryness under reduced pressure(2.7 kPa). 14 g of methyl5-(methylsulfonylmethyl)thiophene-2-carboxylate are thus obtained in theform of a yellow solid melting around 133° C. [¹H NMR spectrum (400 MHz,(CD₃)₂SO-d6, at a temperature of 373 K, δ in ppm): 3.05 (s, 3H), 4.22(mt, 2H), 4.40 (mt, 2H), 4.98 (broad s, 1H), 7.30 (d, J=3.5 Hz, 1H),7.39 (d, J=8 Hz, 4H), 7.50 (d, J=8 Hz, 4H), 7.66 (d, J=3.5 Hz, 1H)].

[0648] Methyl 5-bromomethylthiophene-2-carboxylate may be preparedaccording to Curtin M. L., Davidsen S. K., Heyman H. R., Garland R. B.,Sheppard G. S., J. Med. Chem., 1998, 41 (1), 74-95.

EXAMPLE 120

[0649] 47 μl of N,N′-diisopropylcarbodiimide, 3.66 mg of4-dimethylaminopyridine and 60 μl of isobutylamine are added to asolution of 163.5 mg of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-hydroxycarbonylthien-5-yl)methylene]azetidinehydrochloride in 3 cm³ of dichloromethane, at room temperature. Themixture is stirred for 18 hours at room temperature and thenchromatographed on a silica gel column (particle size 0.04-0.06 mm),eluting with a dichloromethane and ethyl acetate mixture (90/10 byvolume). 60 mg of1-[bis(4-chlorophenyl)methyl]-3-[2-isobutylaminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidineare thus obtained in the form of a colorless lacquer [¹H NMR spectrum(400 MHz, CDCl₃, δ in ppm): 0.97 (d, J=7 Hz, 6H), 1.88 (mt, 1H), 2.90(s, 3H), 3.25 (t, J=7 Hz, 2H), 4.08 (mt, 2H), 4.36 (mt, 2H), 4.52 (s,1H), 4.56 (broad t, J=7 Hz, 1H), from 7.20 to 7.40 (mt, 10H)].

[0650]1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-hydroxycarbonylthien-5-yl)methylene]azetidinehydrochloride may be prepared in the following manner: 250 cm³ ofconcentrated hydrochloric acid are added to a solution of 14 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidinein 250 cm³ of acetic acid, at room temperature. The mixture is stirredfor 38 hours at a temperature of 50° C. and is then concentrated todryness under reduced pressure (2.7 kPa). Three times, the residue issupplemented with 250 cm³ of toluene and concentrated to dryness underreduced pressure (2.7 kPa). After trituration of the residue in 400 cm³of ethyl ether, 14.2 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-hydroxycarbonylthien-5-yl)methylene]azetidinehydrochloride are obtained in the form of a beige powder.

EXAMPLE 121

[0651] 0.37 g of potassium tert-butoxide is added to a solution of 0.92g of 1-[bis(4-chlorophenyl)methyl]-azetidin-3-one and 0.75 g of[(3-methoxycarbonylphenyl)methyl]methylsulfone in 30 cm³ oftetrahydrofuran, under an argon atmosphere, cooled to −70° C., and themixture is stirred for 2 hours at −70° C. 10 cm³ of a 0.1 N solution ofhydrochloric acid are then added and the mixture is allowed to return toroom temperature. After addition of 50 cm³ of ethyl acetate, thereaction mixture is separated after settling out, dried over magnesiumsulfate, filtered and then concentrated to dryness under reducedpressure (2.7 pKa). The residue is chromatographed on a silica gelcolumn (particle size 0.20-0.06 mm, diameter 3 cm, height 50 cm),eluting at a nitrogen pressure of 0.8 bar with a cyclohexane and ethylacetate mixture (70/30 by volume) and collecting 120 cm³ fractions.Fractions 11 to 18 are combined and then concentrated to dryness underreduced pressure (2.7 kPA). The residue is crystallized from 10 cm³ ofisopropyl ether and 30 cm³ of pentane. 0.30 g of1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-olis thus obtained in the form of a white solid [¹H NMR spectrum (400 MHz,CDCl₃, δ in ppm): 2.73 (s, 3H), 3.05 (AB, J=9 Hz, 2H), 3.27 (d, J=9 Hz,1H), 3.63 (s, 1H), 3.79 (d, J=9 Hz, 1H), 3.95 (s, 3H), 4.32 (s, 1H),4.59 (s, 1H), from 7.15 to 7.35 (mt, 8H), 7.51 (t, J=8 Hz, 1H), 7.94(broad d, J=8 Hz, 1H), 8.10 (broad d, J=8 Hz, 1H), 8.32 (broad s, 1H))].

EXAMPLE 122

[0652] By carrying out the operation according to the procedure ofExample 1, starting with 0.66 g of methyl(pyridin-4-ylmethyl)sulfone and1.18 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 0.20 g of a whitesolid is obtained after purification on a silica gel column (particlesize 0.20-0.06 mm, diameter 3 cm, height 50 cm), at a nitrogen pressureof 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 byvolume) as eluent and collecting 120 cm³ fractions. The solid is takenup in 20 cm³ of diisopropyl ether. After filtration, draining anddrying, 0.16 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS)]-azetidin-3-olis obtained [¹H NMR spectrum (400 MHz, CDCl₃,δ in ppm): 2.76 (s, 3H),3.03 (AB, J=9 Hz, 2H), 3.27 (d, J=9 Hz, 1H), 3.53 (s, 1H), 3.83 (d, J=9Hz, 1H), 4.32 (s, 1H), 4.51 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.63(d, J=6 Hz, 2H), 8.68 (d, J=6 Hz, 2H)].

[0653] Methyl(pyridin-4-ylmethyl)sulfone may be prepared according tothe reference JP43002711.

EXAMPLE 123

[0654] By carrying out the operation according to the procedure ofExample 1, starting with 0.47 g of methyl(pyridin-3-ylmethyl)sulfone and0.83 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one, 0.50 g of a whitesolid is obtained after purification on a silica gel column (particlesize 0.20-0.06 mm, diameter 3 cm, height 50 cm), at a nitrogen pressureof 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 byvolume) as eluent and collecting 120 cm³ fractions. The solid is takenup in 30 cm³ of diisopropyl ether. After filtration, draining anddrying, 0.40 g of1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)methyl-(RS)]-azetidin-3-olis obtained [¹H NMR spectrum (300 MHz, CDCl₃, δ in ppm): 2.77 (s, 3H),3.03 (AB, J=9 Hz, 2H), 3.28 (d, J=9 Hz, 1H), 3.66 (s, 1H), 3.83 (d, J=9Hz, 1H), 4.33 (s, 1H), 4.55 (s, 1H), from 7.20 to 7.30 (mt, 8H), 7.37(dd, J=8 and 5 Hz, 1H), 8.16 (dt, J=8 and 2 Hz, 1H), 8.68 (dd, J=5 and1.5 Hz, 1H), 8.83 (d, J=2 Hz, 1H)].

[0655] Methyl(pyridin-3-ylmethyl)sulfone may be prepared according tothe reference JP43002711.

EXAMPLE 124

[0656] 0.0388 cm³ of N-(3-aminopropyl)morpholine is added, at the sametemperature, to a suspension of 150 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid activated on TFP resin (165 AM) in 3 cm³ of dichloromethane,pre-stirred for 90 minutes at a temperature close to 20° C. Thesuspension is stirred at a temperature close to 20° C. for 22 hours andthen filtered on sintered glass. The solid residue is rewashed withtwice 1.5 cm³ of dichloromethane. The filtrates are combined andconcentrated to dryness under reduced pressure (2.7 kPa) at atemperature close to 400C. 60 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamideare thus obtained in the form of a pale yellow foam.

[0657]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamidemay also be prepared in the following manner: 0.083 cm³ ofN-(3-aminopropyl)morpholine, 110 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 5 mg of4-dimethylaminopyridine are successively added to a solution of 300 mgof3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid in 10 cm³ of anhydrous dichloromethane (over calcium chloride) and5 cm³ of dimethylformamide, under an inert atmosphere of nitrogen, at atemperature close to 20° C. The solution obtained is stirred at atemperature close to 20° C. for about 22 hours and then concentrated todryness under reduced pressure (0.27 kPa) at a temperature close to 40°C. The solid residue is taken up in 25 cm³ of dichloromethane and washedwith twice 20 cm³ of a saturated aqueous sodium bicarbonate solution.After separation after settling out, the organic phase is dried overmagnesium sulfate, filtered and concentrated to dryness under reducedpressure (2.7 kPa) at a temperature close to 40° C. 400 mg of a yellowoil are thus obtained, which oil is purified by chromatography undernitrogen pressure (0.8 bar) on 60 cm³ of silica (0.040-0.063 mm)contained in a column 2.2 cm³ in diameter, eluting with amethanol/dichloromethane mixture (2-98 by volume). The fractionscontaining only the desired product are combined and concentrated todryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours. 130 mgof3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-morpholin-4-ylpropyl)benzamideare thus obtained in the form of a white crystalline powder [¹H NMRspectrum (300 MHz, (CD₃)₂SO-d6, δ in ppm): 1.68 (mt, 2H), from 2.25 to2.40 (mt, 6H), 2.97 (s, 3H), from 3.20 to 3.35 (mt, 2H), 3.57 (t, J=4.5Hz, 4H), 3.81 (mt, 2H), 4.22 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz,4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad S,1H), 7.86 (broad d, J=8 Hz, 1H), 8.53 (t, J=5.5 Hz, 1H)].

EXAMPLE 125

[0658] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.033 cm³ ofN,N-dimethyl-1,3-propanediamine. 52 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 1.65 (mt, 2H), 2.18 (s, 6H), from 2.20 to2.35 (mt, 2H), 2.98 (s, 3H), from 3.25 to 3.45 (mt, 2H), 3.82 (mt, 2H),4.23 (mt, 2H), 4.80 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz,4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8Hz, 1H), 8.57 (t, J=5.5 Hz, 1H)].

EXAMPLE 126

[0659] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0333 cm³ of 1-(aminoethyl)pyrrolidine.39 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamideare thus obtained in the form of a pale yelow powder [¹H NMR spectrum(300 MHz, (CD₃)₂SO-d6 with addition of a few drops of CD₃COOD-d4,δ inppm): from 1.80 to 2.00 (mt, 4H), 2.97 (s, 3H), 3.20 (mt, 6H), 3.57 (t,J=6.5 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.77 (s, 1H), 7.35 (d,J=8.5 Hz, 4H), 7.45 (d, J=8.5 Hz, 4H), from 7.50 to 7.65 (mt, 2H), 7.87(broad s, 1H), 7.90 (broad d, J=7.5 Hz, 1H)].

EXAMPLE 127

[0660] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0333 cm³ of1-(dimethylamino)-2-propylamine. 49 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)-benzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 1.13 (d, J=6.5 Hz, 3H), from 2.10 to 2.25(mt, 1H), 2.15 (s, 6H), 2.38 (dd, J=13 and 8 Hz, 1H), 2.98 (s, 3H), 3.80(mt, 2H), 4.14 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz,4H), from 7.45 to 7.60 (mt, 2H), 7.46 (d, J=8 Hz, 4H), 7.83 (broad s,1H), 7.87 (broad d, J=8 Hz, 1H), 8.16 (broad d, J=8 Hz, 1H)].

EXAMPLE 128

[0661] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.026 cm³ of piperidine. 56 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-piperidin-1-ylbenzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): from 1.45 to 1.70 (mt, 6H), from 2.90 to3.05 (mt, 2H), 2.98 (s, 3H), 3.19 (unresolved complex, 1H), 3.57(unresolved complex, 1H), 3.85 (mt, 2H), 4.23 (mt, 2H), 4.80 (s, 1H),from 7.30 to 7.55 (mt, 12H)].

EXAMPLE 129

[0662] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0265 cm³ of isobutylamine. 46 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-isobutylbenzamideare thus obtained in the form of a white powder [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 0.89 (d, J=7 Hz, 6H), 1.85 (mt, 1H), 2.98(s, 3H), 3.09 (t, J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s,1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60(mt, 2H), 7.84 (broad s, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.51 (t, J=6Hz, 1H)].

EXAMPLE 130

[0663] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0316 cm³ of N-(3-aminopropyl)imidazole.54 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamideare thus obtained in the form of a yellow foam [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 1.97 (mt, 2H), 2.98 (s, 3H), 3.25 (mt, 2H),3.81 (mt, 2H), 4.02 (t, J=7 Hz, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), from6.85 to 6.95 (mt, 2H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H),from 7.50 to 7.60 (mt, 2H), 7.84 (broad S, 1H), 7.88 (broad d, J=8 Hz,1H), 8.56 (t, J=5.5 Hz, 1H)].

EXAMPLE 131

[0664] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.030 cm³ ofN,N-(dimethyl)ethylenediamine. 53 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methane-sulfonylmethyl)-N-(2-dimethylaminoethyl)benzamideare thus obtained in the form of an ochre-colored foam [¹H NMR spectrum(400 MHz, (CD₃)₂SO-d6, δ in ppm): 2.18 (2s, 6H), from 2.35 to 2.45 (mt,2H), 2.98 (s, 3H), from 3.25 to 3.50 (mt, 2H), 3.81 (mt, 2H), 4.23 (mt,2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.43(t, J=6.5 Hz, 1H)].

EXAMPLE 132

[0665] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0141 cm³ of methylhydrazine. 42 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid N′methylhydrazide are thus obtained in the form of a pale yellowfoam [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, δ in ppm): 2.96 (s, 3H),3.18 (broad s, 3H), 3.83 (mt, 2H), 4.22 (mt, 2H), 4.80 (broad s, 2H),from 7.35 to 7.65 (mt, 12H)

EXAMPLE 133

[0666] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0345 cm³ of N-(2-aminoethyl)morpholine.62 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamideare thus obtained in the form of an ochre-colored foam [¹H NMR spectrum(400 MHz, (CD₃)₂SO-d6, δ in ppm): from 2.30 to 2.45 (mt, 4H), 2.46 (t,J=7.5 Hz, 2H), 2.98 (s, 3H), 3.38 (mt, 2H), from 3.50 to 3.65 (mt, 4H),3.82 (mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46(d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.85(dd, J=8 and 2 Hz, 1H), 8.45 (t, J=6.5 Hz, 1H)].

EXAMPLE 134

[0667] The operation is carried out under the conditions described inExample 124 starting with 150 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (165 μM) and 0.0396 cm³ of2-(aminomethyl)-N-ethylpyrrolidine. 58 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamideare thus obtained in the form of an ochre-colored foam.

[0668]3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamidemay also be prepared under the conditions described in Example 126starting with 700 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (770 μM), 0.324 cm³ of triethylamine and 0.25 cm³ of2-(aminomethyl)-N-ethylpyrrolidine. 370 mg of a solid are thus obtained,which solid is purified by chromatography under nitrogen pressure (0.7bar) on 100 cm³ of silica (0.040-0.063 mm) contained in a column 2.5 cmin diameter, eluting with a methanol-dichloromethane mixture (15-85 byvolume). The fractions containing only the desired product are combinedand concentrated to dryness under reduced pressure (0.27 kPa) at 40° C.for 2 hours. 160 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamideare thus obtained in the form of a pale yellow powder [¹H NMR spectrum(400 MHz, (CD₃)₂SO-d6, δ in ppm): 1.04 (t, J=7 Hz, 3H), from 1.50 to1.70 (mt, 3H), 1.78 (mt, 1H), 2.14 (mt, 1H), 2.28 (mt, 1H), 2.59 (mt,1H), 2.83 (mt, 1H), 2.98 (s, 3H), from 3.00 to 3.15 (mt, 2H), from 3.30to 3.45 (mt, 1H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d,J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.86(broad s, 1H), 7.85 (broad d, J=8 Hz, 1H), 8.41 (t, J=6 Hz, 1H)].

EXAMPLE 135

[0669] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 AM) and 0.023 cm³ of neopentylamine. 69 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamideare thus obtained in the form of a pale yellow powder [H NMR spectrum(400 MHz, (CD₃)₂SO-d6, δ in ppm): 0.90 (s, 9H), 2.98 (s, 3H), 3.11 (d,J=6.5 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broads, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.37 (t, J=6.5 Hz, 1H)].

EXAMPLE 136

[0670] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.025 cm³ of aminomethylcyclohexane. 44mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-cyclohexylmethylbenzamideare thus obtained in the form of a pale yellow powder whosecharacteristics are the following [¹H NMR spectrum (400 MHz,(CD₃)₂So-d6, δ in ppm): 0.92 (mt, 2H), 1.17 (mt, 4H), from 1.45 to 1.80(mt, 5H), 2.97 (s, 3H), 3.10 (d, J=6 Hz, 2H), 3.80 (mt, 2H), 4.23 (mt,2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.45to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86 (broad d, J=8 Hz, 1H), 8.47(t, J=6 Hz, 1H)].

EXAMPLE 137

[0671] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM), 0.026 cm³ of triethylamine and 21 mg ofaminomethylcyclopropane hydrochloride. 68 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclopropylmethylbenzamideare thus obtained in the form of a yellow foam [H NMR spectrum (400 MHz,(CD₃)₂SO-d6,δ in ppm): 0.24 (mt, 2H), 0.44 (mt, 2H), 1.03 (mt, 1H), 2.98(s, 3H), 3.15 (t, J=6 Hz, 2H), 3.82 (mt, 2H), 4.23 (mt, 2H), 4.79 (s,1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d, J=8.5 Hz, 4H), from 7.50 to 7.60(mt, 2H), 7.86 (broad s, 1H), 7.89 (broad d, J=8 Hz, 1H), 8.64 (t, J=6Hz, 1H)].

EXAMPLE 138

[0672] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.023 cm³ of 2-methylbutylamine. 49 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-methylbutyl)benzamideare thus obtained [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, δ in ppm):from 0.80 to 0.95 (mt, 6H), from 1.05 to 120 (mt, 1H), 1.41 (mt, 1H),1.64 (mt, 1H), 2.98 (s, 3H), 3.06 (mt, 1H), 3.19 (mt, 1H), 3.81 (mt,2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz,4H), from 7.35 to 7.60 (mt, 2H), 7.84 (broad s, 1H), 7.87 (broad d, J=8Hz, 1H), 8.49 (t, J=5.5 Hz, 1H)].

EXAMPLE 139

[0673] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 0.028 cm³ of 2-methylphenethylamine. 42mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-phenylpropyl)benzamideare thus obtained in the form of a yellow paste [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 1.24 (d, J=7 Hz, 3H), 2.97 (s, 3H), 3.07(mt, 1H), from 3.20 to 3.50 (mt, 2H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.80(s, 1H), from 7.10 to 7.40 (mt, 5H), 7.38 (d, J=8 Hz, 4H), 7.47 (d, J=8Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.77 (broad s, 1H), 7.79 (broad d,J=8 Hz, 1H), 8.55 (t, J=6 Hz, 1H)].

EXAMPLE 140

[0674] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 AM) and 0.020 cm³ oftetrahydrofurfurylmethylamine. 42 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methane-sulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamideare thus obtained in the form of a yellow paste [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 1.58 (mt, 1H), from 1.75 to 2.00 (mt, 3H),2.98 (s, 3H), from 3.20 to 3.40 (mt, 2H), 3.63 (mt, 1H), 3.77 (mt, 1H),3.82 (mt, 2H), 3.98 (mt, 1H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8Hz, 4H), 7.46 (d, J=8 Hz, 4H), from 7.50 to 7.60 (mt, 2H), 7.84 (broads, 1H), 7.88 (broad d, J=8 Hz, 1H), 8.60 (t, J=6 Hz, 1H)].

EXAMPLE 141

[0675] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 39 mg of 2,2-diphenylethylamine. 39 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamideare thus obtained in the form of a yellow paste [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 2.95 (s, 3H), 3.77 (mt, 2H), 3.90 (dd, J=8and 6.5 Hz, 2H), 4.22 (mt, 2H), -4.42 (t, J=8 Hz, 1H), 4.79 (s, 1H),from 7.10 to 7.40 (mt, 10H), 7.38 (d, J=8.5 Hz, 4H), from 7.45 to 7.60(mt, 2H), 7.48 (d, J=8.5 Hz, 4H), 7.70 (mt, 2H), 8.56 (t, J=6.5 Hz,1H)].

EXAMPLE 142

[0676] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM) and 19 mg of 2-ethylbutylamine. 47 mg of3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-N-(2-ethylbutyl)benzamideare thus obtained in the form of a pale yellow powder [¹H NMR spectrum(400 MHz, (CD₃)₂SO-d6, δ in ppm): 0.86 (t, J=7 Hz, 6H), from 1.20 to1.40 (mt, 4H), 1.50 (mt, 1H), 2.98 (s, 3H), 3.19 (t, J=6 Hz, 2H), 3.82(mt, 2H), 4.24 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8.5 Hz, 4H), 7.46 (d,J=8.5 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H), 7.86(broad d, J=8 Hz, 1H), 8.42 (t, J=6 Hz, 1H)].

EXAMPLE 143

[0677] The operation is carried out under the conditions described inExample 124 starting with 110 mg of activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin (121 μM), 0.026 cm³ of triethylamine and 39 mg of4-aminomethylcyclohexanecarboxylic acid methyl ester hydrochloride. 47mg of4-{[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylicacid methyl ester are thus obtained in the form of a pale yellow paste[¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, δ in ppm): from 0.90 to 1.05(mt, 2H), from 1.20 to 1.40 (mt, 2H), 1.52 (mt, 1H), from 1.70 to 2.00(mt, 4H), 2.27 (mt, 1H), 2.98 (s, 3H), 3.12 (t, J=6.5 Hz, 2H), 3.60 (s,3H), 3.80 (mt, 2H), 4.23 (mt, 2H), 4.79 (s, 1H), 7.36 (d, J=8 Hz, 4H),7.46 (d, J=8 Hz, 4H), from 7.45 to 7.60 (mt, 2H), 7.83 (broad s, 1H),7.87 (broad d, J=8 Hz, 1H), 8.50 (t, J=6 Hz, 1H)].

[0678] Activated3-({1-[bis(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin may be prepared under the following conditions: 1.18 gof3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid is added, at the same temperature, to a suspension of 1.07 g of TFPresin (free phenol function, 1.1 mmol/g, that is to say 1.17 mM) in 15cm³ of anhydrous dimethylformamide, prestirred for 10 minutes at atemperature close to 20° C. After stirring for 10 minutes at atemperature close to 20° C., 14 mg of 4-dimethylaminopyridine are addedand then after stirring for 10 minutes at the same temperature, 0.185cm³ of 1,3-diisopropylcarbodiimide. After stirring for 23 hours at atemperature close to 20° C., the suspension is filtered and the resin iswashed with 45 cm³ of dimethylformamide, 45 cm³ of tetrahydrofuran, 45cm³ of dichloromethane, and then dried under vacuum to constant weight.1.5 g of activated3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid on TFP resin are thus obtained in the form of a pale yellow resin.

[0679] The TFP resin (structure below) may be prepared in the followingmanner:

[0680] 492 mg of diisopropylcarbodiimide, 819.3 mg of2,3,5,6-tetrafluoro-4-hydroxybenzoic acid and 50 mg of4-dimethylaminopyridine are successively added to a suspension of 2 g ofcommercially available aminomethyl polystyrene resin (0.39 mmol/g; 0.78mmol) in 15 cm³ of dimethylformamide, prestirred for 5 minutes at atemperature close to 20° C. After stirring for about 20 hours at atemperature close to 20° C., the suspension is filtered and the resin isrinsed with three times 20 cm³ of dimethylformamide, three times 20 cm³of tetrahydrofuran and three times 20 cm³ of dichloromethane. The resinobtained is dried under reduced pressure at a temperature close to 40°C. The resin obtained is then stirred, at a temperature close to 20° C.,for about 20 hours, in suspension in a piperidine/dimethylformamidemixture (10/90 by volume). The suspension is filtered and the resin isrinsed with three times 20 cm³ of dimethylformamide, three times 20 cm³of tetrahydrofuran and three times 20 cm³ of dichloromethane. The resinobtained is dried under reduced pressure at a temperature close to 40°C. and is used as it is.

EXAMPLE 144

[0681] A solution of 76 mg of(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamicacid tert-butyl ester in 2.5 cm³ of formic acid is stirred for 1 hour ata temperature close to 45° C. The reaction medium is concentrated todryness under reduced pressure (5 kPa) at a temperature close to 30° C.,taken up in 10 cm³ of ethyl acetate and alkalinized with 10 cm³ of asaturated aqueous sodium bicarbonate solution. After separating aftersettling out, the organic phase is washed with 10 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 51 mg of2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanoneare thus obtained in the form of a beige lacquer [¹H NMR spectrum (300MHz, CDCl₃, δ in ppm): from 1.95 to 2.25 (broad unresolved complex, 2H),2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), from 3.50 to 3.60 (mt, 2H),3.56 (broad s, 2H), from 3.75 to 3.90 (mt, 4H), 4.34 (mt, 2H), 4.50 (s,1H), 6.84 (broad d, J=8 Hz, 1H), 6.91 (dd, J=8 and 2 Hz, 1H), 7.01 (mt,1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 145

[0682] 1.02 g of supported EDCI (5 mM), 44 mg of N-Boc-glycine and then10 cm³ of dichloromethane are successively added, at a temperature closeto 20° C., to 108.5 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 20 hours at a temperature close to 20° C., thereaction mixture is filtered on sintered glass. The resin is rinsed withthree times 5 cm³ of dichloromethane. The combined filtrates are washedwith 20 cm³ of water, dried over magnesium sulfate, filtered on sinteredglass and concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 40° C. 143 mg of(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamicacid tert-butyl ester are thus obtained in the form of a cream-coloredlacquer [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, δ in ppm): 1.40 (s, 9H),2.93 (s, 3H), from 3.05 to 3.20 (mt, 4H), 3.57 (mt, 4H), 3.80 (mt, 2H),3.84 (d, J=6 Hz, 2H), 4.19 (mt, 2H), 4.78 (s, 1H), 6.79 (t, J=6 Hz, 1H),6.82 (d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd, J=8 and 2.5 Hz, 1H),7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].

[0683] The supported EDCI reagent is commercially available and may alsobe prepared according to the following reference: M. Desai, L.Stramiello, Tetrahedron Letters, 34, 48, 7685-7688 (1993).

EXAMPLE 146

[0684] A solution of 81 mg of(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester in 2.5 cm³ of formic acid is stirred for 1 hour ata temperature close to 45° C. The reaction mixture is concentrated todryness under reduced pressure (5 kPa) at a temperature close to 30° C.,taken up in 10 cm³ of ethyl acetate and alkalinized with 10 cm³ of -asaturated aqueous sodium bicarbonate solution. After separating aftersettling out, the organic phase is washed with 10 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 58 mg of1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methane-sulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanoneare thus obtained in the form of a beige lacquer [¹H NMR spectrum (300MHz, CDCl₃), δ in ppm): from 1.95 to 2.15 (broad unresolved complex,1H), 2.51 (broad s, 3H), 2.77 (s, 3H), from 3.10 to 3.30 (mt, 4H), 3.49(broad s, 2H), 3.58 (mt, 2H), from 3.75 to 3.90 (mt, 4H), 4.33 (mt, 2H),4.49 (s, 1H), 6.83 (broad d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2 Hz, 1H),7.00 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 147

[0685] 1.02 g of supported EDCI (5 mM), 47.3 mg of N-Boc-sarcosine andthen 10 cm³ of dichloromethane are successively added, at a temperatureclose to 20° C., to 108.5 mg of1-[3-({1-[bis-(4-chlorophenyl)-methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 20 hours at a temperature close to 20° C., thereaction mixture is filtered on sintered glass. The resin is rinsed withthree times 5 cm³ of dichloromethane. The combined filtrates are washedwith 20 cm³ of water, dried over magnesium sulfate, filtered on sinteredglass and concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 40° C. 143 mg of(2-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester are thus obtained in the form of a cream-coloredlacquer [¹H NMR spectrum (400 MHz, (CD₃)₂SO-d6, δ in ppm). A mixture ofrotamers is observed at room temperature; 1.31 and 1.41 (2s, 9H intotal), 2.78 and 2.81 (2s, 3H in total), 2.93 (2s, 3H), from 3.10 to3.25 (unresolved complex, 4H), from 3.45 to 3.65 (mt, 4H), 3.80 (mt,2H), 4.06 and 4.09 (2s, 2H in total), 4.19 (mt, 2H), 4.78 (s, 1H), 6.83(broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 7.00 (dd, J=8 and 2.5 Hz,1H), 7.27 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46 (d, J=8 Hz, 4H)].

EXAMPLE 148

[0686] 2 cm³ of dichloromethane and then 11 mg of methyl isothiocyanateare successively added, at a temperature close to 20° C., to 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 6 hours at a temperature close to 20° C., 0.05 cm³ ofwater is added to the reaction mixture. After stirring for 15 minutes atthe same temperature, the reaction medium is dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure (1kPa) at a temperature close to 40° C. 61 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioicacid N-methylamide are thus obtained in the form of a beige lacquer [“HNMR spectrum (400 MHz, CDCl₃), δ in ppm): 2.77 (s, 3H), 3.20 (d, J=5 Hz,3H), 3.32 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.00 (t, J=5.5 Hz, 4H), 4.33(mt, 2H), 4.49 (s, 1H), 5.63 (broad q, J=5 Hz, 1H), 6.80 (d, J=8 Hz,1H), 6.85 (dd, J=8 and 2.5 Hz, 1H), 6.94 (broad s, 1H), from 7.20 to7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].

EXAMPLE 149

[0687] 2 cm³ of dichloromethane and then 11.5 mg of methyl isocyanateare successively added, at a temperature close to 20° C., to 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 4 hours at a temperature close to 20° C., 0.05 cm³ ofwater is added to the mixture. After stirring for 15 minutes at the sametemperature, the reaction medium is dried over magnesium sulfate,filtered on paper and concentrated to dryness under reduced pressure (1kPa) at a temperature close to 40° C. 66 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid N-methylamide are thus obtained in the form of a beige lacquer [¹HNMR spectrum (400 MHz, CDCl₃), δ in ppm): 2.75 (s, 3H), 2.85 (d, J=5 Hz,3H), 3.19 (broad t, J=5.5 Hz, 4H), 3.52 (broad t, J=5.5 Hz, 4H), 3.80(mt, 2H), 4.33 (mt, 2H), 4.45 (broad q, J=5 Hz, 1H), 4.49 (s, 1H), 6.81(d, J=8 Hz, 1H), 6.89 (dd, J=8 and 2.5 Hz, 1H), 6.98 (broad s, 1H), from7.20 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].

EXAMPLE 150

[0688] 2 cm³ of pyridine and then 10.4 mg of methyl chloroformate aresuccessively added, at a temperature close to 20° C., to 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 6 hours at a temperature close to 20° C., thereaction medium is concentrated to dryness under reduced pressure (5kPa) at a temperature close to 30° C. The residue obtained is taken upin 5 cm³ of ethyl acetate and 5 cm³ of water. After separating aftersettling out, the organic phase is washed with 2 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 62 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid methyl ester are thus obtained in the form of a beige lacquer [¹HNMR spectrum (400 MHz, CDCl₃), δ in ppm): 2.75 (s, 3H), 3.15 (broad t,J=5.5 Hz, 4H), 3.62 (mt, 4H), 3.74 (s, 3H), 3.80 (mt, 2H), 4.32 (mt,2H), 4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H),6.99 (broad s, 1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 151

[0689] 32 mg of sodium acetoxyborohydride and then 22 mg ofisobutyraldehyde are successively added, at a temperature close to 20°C., to a solution of 54.25 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazinein 2 cm³ of 1,2-dichloroethane. After stirring for 4 hours at atemperature close to 20° C., 3 cm³ of dichloromethane and 2 cm³ of asaturated aqueous sodium bicarbonate solution are added to the reactionmedium. After separating after settling out, the organic [lacuna] isdried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 63 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazineare thus obtained in the form of a beige lacquer [¹H NMR spectrum (400MHz, CDCl₃), δ in ppm): 0.92 (d, J=7 Hz, 6H), 1.82 (mt, 1H) 2.14 (d, J=8Hz, 2H), 2.54 (t, J=5.5 Hz, 4H), 2.75 (s, 3H), 3.18 (t, J=5.5 Hz, 4H),3.81 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.89(dd, J=8 and 2.5 Hz, 1H), 6.97 (broad s, 1H), from 7.15 to 7.30 (mt,5H), 7.32 (d, J=8 Hz, 4H)].

EXAMPLE 152

[0690] 32 mg of sodium acetoxyborohydride and then 13 mg of acetaldehydeare successively added, at a temperature close to 20° C., to a solutionof 54 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazinein 2 cm³ of 1,2-dichloroethane. After stirring for 21 hours at atemperature close to 20° C., 2 cm³ of a saturated aqueous sodiumbicarbonate solution are added to the reaction medium. After separatingafter settling out, the aqueous phase is reextracted with 2 cm³ ofdichloromethane. The pooled organic phases are dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure (1kPa) at a temperature close to 20° C. 60 mg of a solid residue are thusobtained, which residue is taken up in 2 cm³ of methanol and 0.5 cm³ ofdichloromethane. The solution obtained is deposited on a silica catridge(500 mg of SCX phase). The cartridge is washed with 5 cm³ of methanoland then the expected product is eluted with 5 cm³ of ammoniacalmethanol (2 N) and then with an additional 5 cm³ of methanol. Thefiltrate is concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 30° C. 42 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-ethylpiperazineare thus obtained in the form of a colorless lacquer [¹H NMR spectrum(300 MHz, CDCl₃) δ in ppm): 1.14 (t, J=7.5 Hz, 3H), 2.48 (q, J=7.5 Hz,2H), 2.60 (broad t, J=5 Hz, 4H), 2.77 (s, 3H), 3.22 (broad t, J=5 Hz,4H), 3.82 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broad d, J=8 Hz,1H), 6.91 (dd, J=8 and 2 Hz, 1H), 6.98 (mt, 1H), from 7.20 to 7.40 (mt,9H)].

EXAMPLE 153

[0691] 2 cm³ of pyridine and then 11.5 mg of acetic anhydride aresuccessively added, at a temperature close to 20° C., to 54 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine.After stirring for 23 hours at a temperature close to 20° C., thereaction medium is concentrated to dryness under reduced pressure (1kPa) at a temperature close to 30° C. The residue obtained is taken upin 5 cm³ of ethyl acetate and 2 cm³ of water. After separating aftersettling out, the organic phase is washed with 2 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. 52 mg of4-acetyl1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazineare thus obtained in the form of a beige foam [¹H NMR spectrum (300 MHz,CDCl₃), δ in ppm): 2.16 (s, 3H), 2.77 (s, 3H), from 3.10 to 3.25 (mt,4H), 3.63 (broad t, J=5.5 Hz, 2H), 3.78 (broad t, J=5.5 Hz, 2H), 3.82(mt, 2H), 4.34 (mt, 2H), 4.50 (s, 1H), 6.84 (broad d, J=8 Hz, 1H), 6.92(dd, J=8 and 2 Hz, 1H), 7.02 (mt, 1H), from 7.20 to 7.40 (mt, 9H)].

EXAMPLE 154

[0692] 511 mg of supported EDCI (2.5 mM), 11.5 mg of N,N-dimethylglycineand then 5 cm³ of dichloromethane are successively added, at atemperature close to 20° C., to 54 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)-phenyl]piperazine.After stirring for 24 hours at a temperature close to 20° C., 35 mg ofN,N-dimethylglycine are added. After stirring for 96 hours at atemperature close to 20° C. ,the reaction mixture is filtered onsintered glass. The resin is rinsed with three times 2.5 cm³ ofdichloromethane. The combined filtrates are washed with 10 cm³ of water,dried over magnesium sulfate, filtered and concentrated to dryness underreduced pressure (5 kPa) at a temperature close to 20° C. 53 mg of1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanoneare thus obtained in the form of a beige foam [¹H NMR spectrum (400 MHz,(CD₃)₂SO-d6, δ in ppm): 2.20 (s, 6H), 2.94 (s, 3H), 3.12 (s, 2H), 3.16(mt, 4H), 3.58 (mt, 2H), 3.68 (mt, 2H), 3.80 (mt, 2H), 4.19 (mt, 2H),4.78 (s, 1H), 6.81 (broad d, J=8 Hz, 1H), 6.93 (broad s, 1H), 6.99 (dd,J=8 and 2.5 Hz, .H), 7.26 (t, J=8 Hz, 1H), 7.36 (d, J=8 Hz, 4H), 7.46(d, J=8 Hz, 4H)].

EXAMPLE 155

[0693] A solution of 320 mg of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester in 5 cm³ of formic acid is stirred for 5 hours ata temperature close to 20° C., and then for 1 hour at a temperatureclose to 450C. The reaction medium is concentrated to dryness underreduced pressure (5 kPa) at a temperature close to 30° C., taken up in20 cm³ of ethyl acetate and alkalinized with 10 cm³ of a saturatedaqueous sodium bicarbonate solution. After separating after settlingout, the organic phase is washed with three times 10 cm³ of water, driedover magnesium sulfate, filtered and concentrated to dryness underreduced pressure (1 kPa) at a temperature close to 40° C. The residueobtained is purified by depositing, in solution in a minimum ofdichloromethane, on silica gel deposited on a plate [(gel 0.5 mm thick,5 plates of 20 p 20 cm, eluent: dichloromethane-methanol (80-20 byvolume)]. The zone corresponding to the adsorbed desired product,located with UV rays, is scraped and the silica recovered is washed onsintered glass with a dichloromethanemethanol mixture (75-25 by volume).The filtrates are combined and concentrated to dryness under reducedpressure (1 kPa) at a temperature close to 30° C. 180 mg of1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine are thus obtained in the form of a white powder [¹HNMR spectrum (300 MHz, CDCl₃, δ in ppm): 2.77 (s, 3H), 3.05 (mt, 4H),3.16 (mt, 4H), 3.81 (mt, 2H), 4.33 (mt, 2H), 4.49 (s, 1H), 6.79 (broadd, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H), 6.98 (mt, 1H), from 7.20to 7.40 (mt, 9H)].4-[3-({1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 4starting with 1.32 g of4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)phenyl]piperazinel-1-carboxylicacid tert-butyl ester, 0.232 cm³ of methanesulfonyl chloride and 0.733 gof 4-dimethylaminopyridine, the residue obtained is purified bychromatography on a silica gel column (particle size 0.063-0.200 mm,diameter 2 cm, height 25 cm) at atmospheric pressure with adichloromethane-methanol mixture (99.5-0.5 by volume) as eluent andcollecting 15 cm³ fractions. The fractions containing the desiredproduct are combined and concentrated to dryness under reduced pressure(5 kPa) at a temperature close to 300C. 0.86 g of4-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester is thus obtained in the form of a white foam [¹HNMR spectrum (400 MHz, CDCl₃, δ in ppm): 1.50 (s, 9H), 2.77 (s, 3H),3.14 (t, J=5 Hz, 4H), 3.57 (t, J=5 Hz, 4H), 3.81 (mt, 2H), 4.34 (mt, 2H)4.49 (s, 1H), 6.81 (d, J=8 Hz, 1H), 6.90 (dd, J=8 and 2.5 Hz, 1H), 6.99(broad s, 1H), from 7.20 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].

[0694]4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester may be prepared in the following manner: oncarrying out the operation according to the procedure of Example 1starting with 0.886 g of4-(3-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tert-butylester, 0.765 g of 1-[bis-(4-chlorophenyl)methyl]-azetidin-3-one and 1.72cm³ of a 1.6 M solution of n-butyllithium in hexane, 1.37 g of4-[3-({1-[bis-(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester are obtained in the form of a beige powder.

[0695] 4-(3-Methanesulfonylmethylphenyl)piperazine-1-carboxylic acidtert-butyl ester may be prepared in the following manner: on carryingout the operation according to the procedure of Example 10 starting with1.55 g of 4-(3-chloromethylphenyl)piperazine-1-carboxylic acidtert-butyl ester and 0.766 g of sodium methanesulfinate, 0.9 g of4-(3-methanesulfonylmethylphenyl)piperazine-1-carboxylic acid tert-butylester is obtained in the form of a beige powder.4-(3-Chloromethylphenyl)piperazine-1-carboxylic acid tert-butyl estermay be prepared in the following manner: by reacting 16.4 g of4-(3-hydroxymethylphenyl)piperazine-1-carboxylic acid tert-butyl esterin 150 cm³ of dichloromethane, at a temperature close to 20° C., with 29cm³ of diisopropylethylamine and 8.7 cm³ of methanesulfonyl chloride, 15g of 4-(3-chloromethylphenyl)piperazine-1-carboxylic acid tert-butylester are obtained in the form of a beige powder after purification on achromatographic column (silica 0.063-0.200 mm, diameter 6 cm, height 45cm, 100 cm³ fractions), eluting with dichloromethane.

[0696] 4-(3-Hydroxymethylphenyl)piperazine-1-carboxylic acid tert-butylester may be prepared in the following manner: by reacting 15.8 g oftert-butyl esters of 4-(3-butoxycarbonylphenyl)piperazine-1-carboxylicand 4-(3-n-butyloxycarbonylphenyl)piperazine-1-carboxylic acids insolution in 500 cm³ of anhydrous THF, at a temperature close to −10° C., with 102 cm³ of diisobutylaluminum hydride in solution in toluene (20%by weight), 12.8 g of 4-(3-hydroxymethylphenyl)piperazine-1-carboxylicacid tert-butyl ester are obtained in the form of a beige oil.

[0697] The mixture of tert-butyl esters of4-(3-ethoxycarbonylphenyl)piperazine-1-carboxylic and4-(3-n-butyloxycarbonylphenyl)piperazine-1-carboxylic acids may beprepared according to the method described in patent WO 9726250.

EXAMPLE 156

[0698] On carrying out the operation according to Example 38 (method 2)starting with 0.3 g of3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl(RS)]azetidineand 105 mg of lithium hydroxide monohydrate in 10 cm³ of acetonitrile,at a temperature close to 70° C., 0.24 g of1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidineis obtained in the form of an orange-colored foam [¹H NMR spectrum (300MHz, CDCl₃, δ in ppm): 2.81 (s, 3H), from 3.85 to 3.95 (mt, 2H), 3.89(s, 6H), 4.37 (mt, 2H), 4.67 (s, 1H), 6.84 (tt, J=9 and 2.5 Hz, 1H),6.99 (mt, 2H), 7.50 (d, J=8 Hz, 4H), 7.97 (d, J=8 Hz, 4H)].

EXAMPLE 157

[0699] On carrying out the operation according to the procedure ofExample 40 starting with 4.45 g of (3,5-difluorobenzyl)methylsulfone,6.36 g of 1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-one, 2.18 cm³of acetyl chloride and 17 cm³ of a 1.6 M solution of n-butyllithium inhexane, 10.8 g of3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl(RS)]azetidineare obtained in the form of a pale yellow foam [¹H NMR spectrum (400MHz, (CD₃)₂SO-d6, δ in ppm): 2.03 (s, 3H), 2.96 (s, 3H), from 3.25 to3.40 (mt, 2H), 3.52 (broad d, J=8 Hz, 1H), from 3.75 to 3.90 (mt, 1H),3.82 (s, 3H), 3.83 (s, 3H), 4.72 (s, 1H), 5.36 (s, 1H), 7.27 (d, J=8 Hz,2H), from 7.35 to 7.45 (mt, 2H), 7.43 (d, J=8 Hz, 2H), 7.54 (tt, J=9.5and 2.5 Hz, 1H), 7.81 (d, J=8 Hz, 2H), 7.88 (d, J=8 Hz, 2H)

[0700] 1-[bis(4-methoxycarbonylphenyl)methyl]-azetidin-3-one may beprepared in the same manner as1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]-methyl}azetidin-3-one(Example 110) from 1-[bis(4-methoxycarbonylphenyl)methyl]azetidin-3-ol.

[0701] 1-[bis(4-methoxycarbonylphenyl)methyl]-azetidin-3-ol, may beprepared in the same manner as1-{(R)-(4-chlorophenyl)[4-(methoxycarbonyl)phenyl]-methyl}azetidin-3-ol(Example 110) from bis(4-methoxycarbonylphenyl)methylamine.

[0702] Bis(4-methoxycarbonylphenyl)methylamine may be prepared in thesame manner as methyl 4-[(RS)-amino-(4-chlorophenyl)methyl]benzoate(Example 87) from 4,4′-dimethoxycarbonylbenzophenone.

EXAMPLE 158

[0703] On carrying out the operation according to the procedure ofExample 110 starting with 40 mg of(RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidine,0.25 cm³ of dichloromethane and 0.0196 cm³ of morpholine, 35.8 mg of(RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)methanesulfonylmethylene]azetidin-1-yl}methyl)benzyl]morpholineare obtained in the form of a white foam [¹H NMR spectrum (400 MHz,CDCl₃, δ in ppm): 2.41 (mt, 4H), 2.80 (s, 3H), 3.42 (s, 2H), 3.69 (t,J=4.5 Hz, 4H), 3.84 (mt, 2H), 4.33 (mt, 2H), 4.50 (s, 1H), 6.83 (tt, J=9and 2.5 Hz, 1H), 6.98 (mt, 2H), from 7.20 to 7.40 (mt, 8H)].

[0704](RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidinemay be prepared in the following manner: on carrying out the operationaccording to Example 87 starting with 415 mg of(RS)-1-{(4-(chlorophenyl)[4-(hydroxymethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,5 cm³ of dichloromethane, 0.19 cm³ of methanesulfonyl chloride and 0.53cm³ of diisopropylethylamine, 421.2 mg of(RS)-1-{[4-(chloromethyl)phenyl](4-chlorophenyl)methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl)methylsulfonylmethylene]azetidineare obtained in the form of a cream-colored foam.

EXAMPLE 159

[0705] 25 mg of potassium carbonate and then 0.016 cm³ of morpholine aresuccessively added, at a temperature close to 20° C., under an inertatmosphere of argon, to a solution of 33 mg of1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidinein 2 cm³ of anhydrous acetonitrile. After stirring for 17 hours at atemperature close to 20° C., the reaction medium is diluted with 10 cm³of ethyl acetate and 4 cm³ of water. The separated organic phase iswashed with 4 cm³ of a saturated aqueous sodium chloride solution, driedover magnesium sulfate, filtered on sintered glass and then concentratedto dryness under reduced pressure (1 kPa) at a temperature close to 40°C. The residue obtained is purified by depositing, in solution in aminimum of dichloromethane, on chromatography on silica gel deposited ona plate [(gel 0.5 mm thick, 2 plates of 20 P 20 cm, eluent:dichloromethane-methanol (92.5-7.5 by volume)]. The zone correspondingto the desired product adsorbed, located with UV rays, is scraped andthe silica recovered is washed on sintered glass with adichloromethane-methanol mixture (80-20 by volume). The filtrates arecombined and concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 40° C. 25.2 mg of4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]-phenoxy}butyl)morpholineare obtained in the form of a pale yellow foam [¹H NMR spectrum (400MHz, CDCl₃, δ in ppm): 1.66 (mt, 2H), 1.81 (mt, 2H), 2.40 (t, J=7.5 Hz,2H), 2.46 (mt, 4H), 2.77 (s, 3H), 3.72 (t, J=5 Hz, 4H), 3.84 (mt, 2H),3.96 (t, J=6.5 Hz, 2H), 4.36 (mt, 2H), 4.53 (s, 1H), 6.87 (dd, J=8 and 2Hz, 1H), 6.93 (d, J=8 Hz, 1H), 6.96 (d, J=2 Hz, 1H), from 7.10 to 7.35(mt, 7H), 7.42 (d, J=8 Hz, 4H)].1-Benzhydryl-3-{[3-(4-bromobutoxy)phenyl]-methanesulfonylmethylene}azetidinemay be prepared in the following manner: 0.586 cm³ of 1,4-dibromobutaneand 255 mg of potassium carbonate are successively added at atemperature close to 20° C., under an inert atmosphere of argon, to asolution of 500 mg of1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine in10 cm³ of methylethyl ketone. The reaction mixture is heated at thereflux temperature of the solvent, under an inert atomosphere of argon,for 7 hours and then left at a temperature close to 20° C. for about 4days. The reaction mixtue is filtered on sintered glass covered withcelite. The solid residue is rinsed with ethyl acetate and then thefiltrate is concentrated to dryness under reduced pressure (10 kPa) at atemperature close to 40° C. The brown oil obtained is purified bychromatography at atmospheric pressure on 40 g of silica (0.063-0.200mm) contained in a column 3 cm in diameter, eluting with amethanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10cm³) containing only the desired product are combined and concentratedto dryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours,408.4 mg of1-benzhydryl-3-{[3-(4-bromobutoxy)phenyl]methanesulfonylmethylene}azetidineare thus obtained in the form of a brown foam.

EXAMPLE 160

[0706] 0.110 cm³ of morpholine and then 35 mg of potassium carbonate aresuccessively added, at a temperature close to 20° C., to a solution of45 mg of1-benzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}azetidinein 3.5 cm³ of anhydrous acetonitrile. After stirring for 20 hours at atemperature close to 20° C., the reaction medium is diluted with 40 cm³of ethyl acetate and 10 cm³ of water. The separated organic phase iswashed with 10 cm³ of water, and then twice 10 cm³ of a saturatedaqueous sodium chloride solution, dried over magnesium sulfate, filteredon sintered glass and then concentrated to dryness under reducedpressure (9 kPa) at a temperature close to 40° C. The yellow lacquerobtained is purified by depositing, in solution in a minimum ofdichloromethane, on chromatography on silica gel deposited on a plate[(gel 0.5 mm thick, 2 plates of 20

20 cm, eluent: dichloromethane-methanol (97.5-2.5 by volume)]. The zonecorresponding to the desired product adsorbed, located with UV rays, isscraped and the silica recovered is washed on sintered glass with adichloromethane-methanol mixture (85-15 by volume). The filtrates arecombined and concentrated to dryness under reduced pressure (1 kPa) at atemperature close to 40° C. 33 mg of4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholineare thus obtained in the form of a white foam [¹H NMR spectrum (300 MHz,(CD₃)₂SO-d6, δ in ppm): 1.87 (mt, 2H), 2.37 (mt, 4H), 2.42 (t, J=7.5 Hz,2H), 2.94 (s, 3H), 3.58 (mt, 4H), 3.80 (mt, 2H), 4.02 (t, J=7 Hz, 2H),4.20 (mt, 2H), 4.74 (s, 1H), 6.97 (mt, 3H), 7.22 (t, J=7.5 Hz, 2H), from7.25 to 7.40 (mt, 1H), 7.32 (t, J=7.5 Hz, 4H), 7.48 (d, J=7.5 Hz, 4H)].1-Benzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}azetidinemay be prepared in the following manner: 0.5 cm³ of 1,3-dibromopropaneand 255 mg of potassium carbonate are successively added at atemperature close to 20° C., under an inert atmosphere of argon, to asolution of 500 mg of1-benzhydryl-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine in10 cm³ of methyl ethyl ketone. The reaction mixture is heated at thereflux temperature of the solvent, under an inert atmosphere of argon,for 7 hours, and then left at a temperature close to 20° C. for about 4days. The reaction mixture is filtered on sintered glass covered withcelite. The solid residue is rinsed with ethyl acetate and then thefiltrate is concentrated to dryness under reduced pressure (10 kPa) at atemperature close to 40° C. The brown oil obtained is purified bychromatography at atmospheric pressure on 40 g of silica (0.063-0.200mm) contained in a column 3 cm in diameter, eluting with amethanol-dichloromethane mixture (0.5-99.5 by volume). The fractions (10cm³) containing only the desired product are combined and concentratedto dryness under reduced pressure (0.27 kPa) at 40° C. for 2 hours.511.1 mg ofbenzhydryl-3-{[3-(4-bromopropyloxy)phenyl]methanesulfonylmethylene}azetidineare thus obtained in the form of a brown foam.

[0707] The medicaments according to the invention consists of a compoundof formula (I) or an isomer or a salt of such a compound, in the purestate or in the form of a composition in which it is combined with anyother pharmaceutically compatible product which may be inert orphysiologically active. The medicaments according to the invention maybe used orally, parenterally, rectally or topically.

[0708] As solid compositions for oral administration, tablets, pills,powders (gelatine capsules, sachets) or granules may be used. In thesecompositions, the active ingredient according to the invention is mixedwith one or more inert diluents, such as starch, cellulose, sucrose,lactose or silica, under an argon stream. These compositions may alsocomprise substances other than diluents, for example one or morelubricants such as magnesium stearate or talc, a coloring, a coating(sugar-coated tablet) or a glaze.

[0709] As liquid compositions for oral administration, there may be usedpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents such as water, ethanol, glycerol,vegetable oils or paraffin oil. These compositions may comprisesubstances other than diluents, for example wetting, sweetening,thickening, flavoring or stabilizing products.

[0710] Sterile compositions for parenteral administration may bepreferably solutions which are aqueous or nonaqueous, suspensions oremulsions. As solvent or vehicle, there may be used water, propyleneglycol, polyethylene glycol, vegetable oils, in particular olive oil,injectable organic esters, for example ethyl oleate or other suitableorganic solvents. These compositions may also contain adjuvants, inparticular wetting, isotonizing, emulsifying, dispersing and stabilizingagents. Sterilization may be carried out in several ways, for example byaseptisizing filtration, by incorporating sterilizing agents into thecomposition, by irradiation or by heating. They may also be prepared inthe form of sterile solid compositions which may be dissolved at thetime of use in sterile water or any other injectable sterile medium.

[0711] Compositions for rectal administration are suppositories orrectal capsules which contain, in addition to the active product,excipients such as cocoa butter, semisynthetic glycerides orpolyethylene glycols.

[0712] Compositions for topical administration may be, for example,creams, lotions, collyria, collutoria, nasal drops or aerosols.

[0713] In human therapy, the compounds according to the invention areparticularly useful for the treatment and/or prevention of psychosesincluding schizophrenia, anxiety disorders, depression, epilepsy,neurodegeneration, cerebellar and spinocerebellar disorders, cognitivedisorders, cranial trauma, panic attacks, peripheral neuropathies,glaucomas, migraine, Parkinson's disease, Alzheimer's disease,Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsivedisorder, senile dementia, thymic disorders, Tourette's syndrome,tardive dyskinesia, bipolar disorders, cancers, movement disordersinduced by medicaments, dystonia, endotoxemic shocks, hemorrhagicshocks, hypotension, insomnia, immunological diseases, multiplesclerosis, vomiting, asthma, appetite disorders (bulimia, anorexia),obesity, memory disorders, intestinal transit disorders, in weaning fromchronic treatments and alcohol or drug abuse (opiods, barbiturates,cannabis, cocaine, amphetamine, phencyclide, hallucinogens,benzodiazepines for example), as analgesics or potentiators of theanalgesic activity of the narcotic and normarcotic drugs asantibacterial, antiviral and antiparasitic agents.

[0714] The doses depend on the desired effect, the duration of thetreatment and the route of administration used; they are generallybetween 5 mg and 1000 mg per day orally for an adult with unit dosesranging from 1 mg to 250 mg of active substance.

[0715] In general, the doctor will determine the appropriate dosagedepending on the age, weight and any other factors specific to thesubject to be treated.

[0716] The following examples illustrate the compositions according tothe invention:

EXAMPLE A

[0717] Gelatin capsules containing a dose of 50 mg of active product andhaving the following composition are prepared according to the usualtechnique: Compound of formula (I) 50 mg Cellulose 18 mg Lactose 55 mgColloidal silica  1 mg Sodium carboxymethylstarch 10 mg Talc 10 mgMagnesium stearate  1 mg

EXAMPLE B

[0718] Tablets containing a dose of 50 mg of active product and havingthe following composition are prepared according to the usual technique:Compound of formula (I) 50 mg Lactose 104 mg  Cellulose 40 mg Polyvidone10 mg Sodium carboxymethylstarch 22 mg Talc 10 mg Magnesium stearate  2mg Colloidal silica  2 mg Mixture of hydroxymethylcellulose, glycerin,titanium oxide (72-3.5-24.5) qs 1 finished film- coated tabletcontaining 245 mg

EXAMPLE C

[0719] An injectable solution containing 10 mg of active product andhaving the following composition is prepared: Compound of formula (I) 10mg Benzoic acid 80 mg Benzyl alcohol 0.06 ml Sodium benzoate 80 mgEthanol, 95% 0.4 ml Sodium hydroxide 24 mg Propylene glycol 1.6 ml Waterqs 4 ml

1. A method of treating a condition selected from the group consistingof schizophrenia, anxiety disorders, depression, epilepsy,neurodegeneration, cerebellar and spinocerebellar disorders, cognitivedisorders, cranial trauma, panic attacks, peripheral neuropathies,glaucomas, migraine, Parkinson's disease, Alzeimer's disease,Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsivedisorder, senile dementia, thymic disorders, Tourette's syndrome,tardive dyskinesia, bipolar disorders, cancers, movement disordersinduced by medicaments, dystonia, endotoxemic shocks hemorrhagic shocks,hypotension, insomnia, immunological diseases, multiple sclerosis,vomiting, asthma, appetite disorders (bulimia, anorexia), obesity, andmemory disorders, as well as in weaning from chronic treatments andalcohol or a drug of abuse, as analgesics and as potentiators of theanalgesic activity of the narcotic and normarcotic drugs, this methodcomprising administering to a patient in need of such treatment aneffective amount to treat said condition of a compound of formula:

in which R represents

R¹ represents a methyl or ethyl radical; R₂ represents either anaromatic radical selected from phenyl, naphthyl and indenyl, thesearomatic radicals being nonsubstituted or substituted with one or moresubstituents selected from halogen, alkyl, alkoxy, —CO-alk, hydroxyl,—COOR₅. formyl, trifluoromethyl, trifluoromethylsulfanyl,trifluoromethoxy, nitro, —NR₆R₇, —CO—NH—NR₆R₇, —N(alk)COOR₈, cyano,—CONHR₉, —CO—NR₁₆R₁₇ alkylsulfanyl, hydroxyalkyl, —O-alk-NR₁₂R¹³ andalkylthioalkyl or a heteroaromatic radical selected from benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, indolinyl, indolyl,isochromanyl, isoquinolyl, pyridyl, quinolyl,1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, thiazolyl,and thienyl, these heteroaromatic radicals being nonsubstituted orsubstituted with a substituent selected from halogen, alkyl, alkoxy,—COOR₅, trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy,nitro, —NR₆R₇, —CO—NH—NR₆R₇, cyano, —CONHR₉alkylsulfanyl, hydroxyalkyland alkylthioalkyl; R₃ and R₄, which are identical or different, eachrepresent either an aromatic radical selected from phenyl, naphthyl andindenyl, these aromatic radicals being nonsubstituted or substitutedwith one or more substituents selected from halogen, alkyl, alkoxy,formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, —CO-alk, cyano,—COOR₅′-CONR₁₀R₁₁—CO—NH—NR₆R₇alkylsulfanyl, hydroxyalkyl, -alk-NR₆R₇ andalkylthioalkyl; or a heteroaromatic radical selected from benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, isochromanyl,isoquinolyl, pyrrolyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,thiazolyl and thienyl, these heteroaromatics being nonsubstituted orsubstituted with a substituent selected from halogen, alkyl, alkoxy,hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, —COOR₅,—CO—NH—NR₆R₇, —CONR₁₀R₁₁, -alk-NR₆R₇, alkylsulfanyl, hydroxyalkyl andalkylthioalkyl; R₅ is an alkyl or phenyl radical which is optionallysubstituted with one or more halogens; R₆ and R₇, which are identical ordifferent, represent a hydrogen, alkyl, —COOalk, cycloalkyl,alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or, alternatively,R₆ and R₇ together with the nitrogen atom to which they are attached,form a 3- to 10-membered saturated or unsaturated mono- or bicyclicheterocycle optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with one ormore alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo,hydroxyalkyl, -alk-O-alk or —CO—NH₂ radicals; R₈ represents an alkylradical; R₉ represents a hydrogen or unsubstituted alkyl radical or analkyl radical that is substituted with a dialkylamino, phenyl,cycloalkyl (optionally substituted with —COOalk) or a 3- to 10-memberedsaturated or unsaturated mono- or bicyclic heterocycle containing one ormore heteroatoms selected from oxygen, sulfur and nitrogen and beingoptionally substituted with one or more alkyl radicals; R₁₀ and R₁₁,which are identical or different, each represent a hydrogen atom or analkyl radical or, alternatively, R₁₀ and R_(11,) together with thenitrogen atom to which they are attached, form a 3- to 10-memberedsaturated mono- or bicyclic heterocycle optionally containing anotherheteroatom selected from oxygen, sulfur and nitrogen and are optionallysubstituted with an alkyl radical; R₁₂ and R₁₃, which are identical ordifferent, represent a hydrogen, alkyl or cycloalkyl radical or,alternatively, R₁₂ and R_(13,) together with the nitrogen atom to whichthey are attached, form a 3- to 10-membered saturated mono- or bicyclicheterocycle optionally containing another heteroatom selected fromoxygen, sulfur and nitrogen and being optionally substituted with analkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk or —CO-alk-NR₁₄R₁₅ radical,or a 3- to 10-membered saturated mono- or bicyclic heterocyclecontaining a heteroatom selected from oxygen, sulfur and nitrogen; R₁₄and R₁₅, which are identical or different, represent a hydrogen, alkylor —COOalk radical; R₁₆ and R_(17,) together with the nitrogen atom towhich they are attached, form a 3- to 10-membered saturated mono- orbicyclic heterocycle optionally containing another heteroatom selectedfrom oxygen, sulfur and nitrogen; R′ represents a hydrogen or —CO-alkradical; alk represents an alkyl or alkylene radical, it beingunderstood that the alkyl and alkylene radicals and portions and thealkoxy radicals and portions are in the form of a straight or branchedchain and contain 1 to 6 carbon atoms, or an optical isomer thereof or asalt thereof with an inorganic or organic acid.
 2. The method of claim 1wherein, in the compound of formula (I) according to claim 1, when R₆and R_(7,) together with the nitrogen atom to which they are attached,form a 3- to 10-membered saturated or unsaturated mono- or bicyclicheterocycle, the latter is an azetidinyl, pyrrolidinyl, piperazinyl,piperidyl, morpholinyl, imidazolyl, thiomorpholinyl or furyl ring, theserings being optionally substituted with an alkyl, hydroxyalkyl,-alk-O-alk, —CONH₂, —COalk, —COOalk, oxo, —CSNHalk, —CONHalk or—CO-alk-NR₁₄R₁₅ in which alk, R₁₄ and R₁₅ have the same meanings as inclaim 1, or an optical isomer thereof or a salt thereof with aninorganic or organic acid.
 3. The method of claim 1 wherein, in thecompound of formula (I) according to claim 1, when R₁₀ and R_(11,)together with the nitrogen atom to which they are attached, form a 3- to10-membered saturated mono- or bicyclic heterocycle, said heterocycle isan azetidinyl, pyrrolidinyl, piperazinyl, piperidyl, morpholinyl orthiomorpholinyl ring, these rings being optionally substituted with analkyl.
 4. The method of claim 1 wherein, in the compound of formula (I)according to claim 1, when R₁₂ and R₁₃, together with the nitrogen atomto which they are attached, form a 3- to 10-membered saturated mono- orbicyclic heterocycle, said heterocycle is selected from azetidinyl,pyrrolidinyl, piperazinyl, piperidyl, morpholinyl and thiomorpholinylrings, these rings being optionally substituted with an alkyl, —COalk,—COOalk, —CO—NHalk, —CS—NHalk or —CO-alk-NR₁₄R₁₅ radical or a 3- to10-membered saturated mono- or bicyclic heterocycle containing aheteroatom selected from oxygen, sulfur and nitrogen, alk, R₁₄ and R₁₅having the same meanings as in claim 1, an optical isomer thereof, or asalt thereof with an inorganic or organic acid.
 5. The method of claim 4wherein said heterocycle is a thiomorpholinyl radical.
 6. The method ofclaim 1 wherein, in the compound of formula (I) according to claim 1,when R₁₆ and R_(17,) together with the nitrogen atom to which they areattached, form a 3- to 10-membered saturated mono- or bicyclicheterocycle, said heterocycle is a piperidyl ring, or an optical isomerthereof or a salt thereof with an inorganic or organic acid.
 7. Themethod of claim 1 wherein, in the compound of formula (I) according toclaim 1, R₉ is an alkyl radical substituted with a 3- to 10-memberedsaturated or unsaturated mono- or bicyclic heterocycle selected frompyrrolidinyl, tetrahydrofuryl, morpholinyl and pyrrolyl rings, theserings being optionally substituted with one or more alkyl radicals, anoptical isomer thereof or a salt thereof with an inorganic or organicacid.
 8. The method of claim 1 wherein, in the compound of formula (I)according to claim 1, R represents structure (A) or (B); R′ represents ahydrogen atom or a —COalk radical; R₁ represents a methyl or ethylradical; R₂ represents either an aromatic radical selected from phenyland naphthyl, these aromatic radicals being nonsubstituted orsubstituted with one or more substituents selected from halogen, alkyl,alkoxy, hydroxyl, —COOR₅, trifluoromethyl, trifluoromethylsulfanyl,trifluoromethoxy, —NR₆R₇, —CO—NH—NR₆R₇, cyano, —CONHR₉ alkylsulfanyl,hydroxyalkyl, nitro, —CO—NR₁₆R₁₇, —O-alkNR₁₂R₁₃ and alkylthioalkyl, or aheteroaromatic radical selected from isoquinolyl, pyridyl, quinolyl,1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl and thienyl,these heteroaromatic radicals being unsubstituted or substituted with ahalogen, alkyl, alkoxy, —COOR₅, trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇, —CO—NH—NR₆R₇, cyano,—CONHR , alkylsulfanyl, hydroxyalkyl, nitro or alkylthioalkylsubstituent; R₃ and R₄, which may be identical or different, representeither an aromatic radical selected from phenyl and naphthyl, thesearomatic radicals being nonsubstituted or substituted with one or moresubstituents selected from halogen, alkyl, alkoxy, trifluoromethyl,trifluoromethoxy, —CONR₁₀ R₁₁, -alk-NR₆R₇, hydroxyalkyl, formyl and—COOR₅, or a heteroaromatic radical selected from thiazolyl and thienylrings, these heteroaromatic rings being nonsubstituted or substituted bya halogen, alkyl, alkoxy, —CONR₁₀R₁₁, -alk-NR₆R₇, hydroxyalkyl or—COOR₅; R₅ is alkyl or phenyl which is optionally substituted with oneor more halogens; R₆ and R₇, which may be identical or different,represent a hydrogen, alkyl, —COOalk, cycloalkyl, alkylcycloalkyl,alk-O-alk or hydroxyalkyl radical or, alternatively, R₆ and R_(7,)together with the nitrogen atom to which they are attached, form a 3- to10-membered saturated or unsaturated mono- or bicyclic heterocycleoptionally containing another heteroatom selected from oxygen, sulfurand nitrogen and being optionally substituted with one or more alkyl,—COalk, —COOalk, —CO—NHalk, —CS—NHalk, —CO-alk-NR₁₄R₁₅, oxo,hydroxyalkyl, alk-O-alk or —CO—NH₂ radicals; R₉ represents a hydrogen orunsubstituted alkyl radical or an alkyl radical substituted withdialkylamino, phenyl, cycloalkyl (optionally substituted with —COOalk)or a 3- to 10-membered saturated or unsaturated mono- or bicyclicheterocycle containing one or more heteroatoms selected from oxygen,sulfur and nitrogen and being optionally substituted with one or morealkyl radicals; R₁₀ and R₁₁, which may be identical or different,represent a hydrogen or alkyl radical or, alternatively, R₁₀ and R_(11,)together with the nitrogen atom to which they are attached, form a 3- to10-membered saturated mono- or bicyclic heterocycle optionallycontaining another heteroatom selected from oxygen, sulfur and nitrogenand being optionally substituted with an alkyl radical; R₁₂ and R₁₃,which may be identical or different, represent a hydrogen, alkyl orcycloalkyl radical or, alternatively, R₁₂ and R₁₃, together with thenitrogen atom to which they are attached, form a 3- to 10-memberedsaturated mono- or bicyclic heterocycle optionally containing anotherheteroatom selected from oxygen, sulfur and nitrogen and beingoptionally substituted with an alkyl, —COalk, —COOalk, —CO—NHalk,—CS—NHalk or —CO-alk-NR₁₄R₁₅ radical, or a 3- to 10-membered saturatedmono- or bicyclic heterocycle containing a heteroatom selected fromoxygen, sulfur and nitrogen; R₁₄ and R₁₅, which may be identical ordifferent, represent a hydrogen, alkyl or —COOalk radical; R₁₆ andR_(17,) together with the nitrogen atom to which they are attached, forma 3- to 10-membered saturated mono- or bicyclic heterocycle optionallycontaining another heteroatom selected from oxygen, sulfur and nitrogen;alk represents an alkyl or alkylene radical, it being understood thatthe alkyl and alkylene radicals and portions and the alkoxy radicals andportions are in the form of a straight or branched chain and contain 1to 6 carbon atoms, an optical isomer thereof or a salt thereof with aninorganic or organic acid.
 9. The method of claim 1 wherein saidcompound is selected from:1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)]azetidin-3-ol,3-acetoxy-1-[bis-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylulfonyl)methyl)methylsulfonyl-methyl-(RS)]azetidine,their optical isomers and their salts with an inorganic or organic acid.10. The method of claim 1 wherein, in the compound of formula (I)according to claim 1, R represents structure (A) or (B); R′ representinga hydrogen or —COalk radical; R₁ represents a methyl or ethyl radical;R₂ represents either (I) an aromatic selected from naphthyl, phenyl,phenyl substituted with one or more halogen, alkyl, alkoxy, hydroxyl,—COOR₅, (in which R₅, represents an alkyl or phenyl radical optionallysubstituted with several halogens) trifluoromethyl,trifluoromethylsulfanyl, trifluoromethoxy, —NR₆R₇ (in which R₆ and R₇,which may be identical or different, represent a hydrogen, alkyl or—COOalk radical or, alternatively, R₆ and R₇, together with the nitrogenatom to which they are attached, form a heterocycle selected frompyrrolidinyl, piperidyl, piperazinyl and piperazinyl substituted withone or more alkyl, —COalk, —COOalk, —CO—NHalk, —CS—NHalk or—CO-alk-NR₁₄R₁₅ radicals (in which R₁₄ and R₁₅, which may be identicalor different, represent a hydrogen or alkyl radical), —CO—NH—NR₆R, (inwhich R₆ and R₇, which may be identical or different, represent ahydrogen or alkyl radical or, alternatively, R₆ and R₇, together withthe nitrogen atom to which they are attached, form a heterocycleselected from piperidyl, pyrrolyl, piperazinyl and piperazyl substitutedwith one or more alkyl radicals), cyano, —CONHR₉, (in which R₉,represents a hydrogen or unsubstituted alkyl radical or an alkyl radicalsubstituted with dialkylamino, phenyl or cycloalkyl (optionallysubstituted with —COOalk)) or (II) a heterocycle selected frompyrrolidinyl (optionally substituted with alkyl), tetrahydrofuryl ormorpholinyl), alkylsulfanyl, hydroxyalkyl, nitro, —CO—NR₁₆R₁₇, (in whichR₁₆ and R₁₇, together with the nitrogen atom to which they are attached,form a piperidyl ring), —O-alkNR₁₂R₁₃ (in which R₁₂ and R₁₃, togetherwith the nitrogen atom to which they are attached, form a morpholinoring) and alkylthioalkyl, or (III) a heteroaromatic selected fromisoquinolyl, pyridyl, quinolyl, 1,2,3,4-tetrahydroisoquinolyl,1,2,3,4-tetrahydroquinolyl,thienyl, and thienyl substituted with a—COOR₅ (in which R⁵ represents an alkyl radical) or —CONHR₉ (in which R₉represents an alkyl radical); R₃ and R⁴, which may be identical ordifferent, represent either (IV) an aromatic selected from phenyl andphenyl substituted with one or more substituents selected from halogen,alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, hydroxyalkyl, formyl,—COOR₅, (in which R₅ is an alkyl radical), —CONR₁₀R₁₁ (in which R₁₀ andR₁₁, which may be identical or different, represent a hydrogen or alkylradical), -alk-NR₆R₇ (in which R₆ and R₇, which may be identical ordifferent, represent a hydrogen, alkyl, cycloalkyl, -alk-O-alk orhydroxyalkyl radical or, alternatively, R₆ and R₇, together with thenitrogen atom to which they are attached, form a heterocycle selectedfrom piperidyl (optionally substituted with alkyl or oxo), pyrrolidinyl(optionally substituted with alkyl, hydroxyalkyl, -alk-O-alk or—CO—NH₂), thiomorpholinyl, morpholinyl, pyrrolyl, piperazinyl optionallysubstituted with oxo, alkyl, hydroxyalkyl, and —COOR₅ (in which R₅ is analkyl radical), or (V) a heteroaromatic selected from thiazolyl andthienyl; alk represents an alkyl or alkylene radical, it beingunderstood that the alkyl and alkylene radicals and portions and thealkoxy radicals and portions are in the form of a straight or branchedchain and contain 1 to 6 carbon atoms, an optical isomer thereof or asalt thereof with an inorganic or organic acid.
 11. The method of claim1 wherein said compound is selected from:1-benzhydryl-3-[(methylsulfonyl)(phenyl)methylene]-azetidine,1-benzhydryl-3-[(3-methylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-chlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(2,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(2,3-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-fluorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-bromophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-iodophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(methylsulfonyl)(3-trifluoromethoxy-phenyl)methylene]azetidine,1-benzhydryl-3-[(3-methylsulfonyl)(3-trifluoromethyl-phenyl)methylene]azetidine,1-benzhydryl-3-{[3,5-bis(trifluoromethyl)phenyl]-(methylsulfonyl)methylene}azetidine,1-benzhydryl-3-[(3,5-dibromophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-carbamoylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(methylsulfonyl)(naphth-1-yl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-methoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-methylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,(R)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,(S)-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-1-[(4-methoxyphenyl)(phenyl)methyl]azetidine,1-[bis(4-trifluoromethoxyphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,and1-[bis(4-trifluoromethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine.12. The method of claims 1, wherein said compound is selected from:1-[bis(4-chlorophenyl)methyl]-3-{[3,5-bis-(trifluoromethyl)phenyl]methylsulfonylmethylene}-azetidine,(RS)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,(R)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,(S)-1-[(4-chlorophenyl)(2,4-dichlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,(RS)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-(hydroxymethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-(pyrrolidylmethyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(3,3-dimethylpiperidin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(thiomorpholin-4-ylmethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(N-ethyl-N-cyclohexylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,and1-{{(RS)-(4-chlorophenyl){4-[(4-ethoxycarbonyl-piperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,their optical isomers and their salts with an inorganic or organic acid.13. The method of claim 1, wherein said compound is selected from:1-{{(R)-(4-chlorophenyl){4-[(4-ethoxycarbonyl-piperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{{(S)-(4-chlorophenyl){4-[(4-ethoxycarbonyl-piperazinyl)methyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(N-cyclopropyl-N-propyl-aminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(diisopropylaminomethyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{{(RS)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{{(R)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{{(S)-(4-chlorophenyl){4-[bis-(2-methoxyethyl)aminomethyl]phenyl}methyl}}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(di-n-propylamino-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(di-n-propylamino-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(di-n-propylamino-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)-methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(piperidin-1-ylmethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,and1-{(RS)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,their optical isomers and their salts with an inorganic or organic acid.14. The method of claim 1, wherein said compound is selected from:1-{(R)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(4-methylpiperazin-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(morpholin-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(diethylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(diethylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(diethylaminomethyl)-phenyl]methyl}-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(piperazin-2-on-4-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methyl-sulfonyl)methylene]azetidine,1-{(RS)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(R)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-{(S)-(4-chlorophenyl)[4-(imidazol-1-yl-methyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-(N,N-dimethylcarbamoyl)phenyl]methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-{(4-chlorophenyl)[4-(N-ethylcarbamoyl)phenyl]-methyl}-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,(R)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,and(S)-1-[(4-carbamoylphenyl)(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,their optical isomers and their salts with an inorganic or organic acid.15. The method of claim 1, wherein said compound is selected from:1-[bis(4-chlorophenyl)methyl]-3-[(3,5-dichlorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-methylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(3-methylsulfanylmethyl)phenyl)]-(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-cyanophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-carbamoylphenyl)-(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxyphenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxyphenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-pyrrolidinylphenyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-hydroxymethylphenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]3-{(methylsulfonyl)[3-(N-methylene}azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)-(3-trifluoromethylsulfanylphenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)-(methylsulfonyl)methylene]azetidine,1-[bis(2-fluorophenyl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(3-fluorophenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,(RS)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-[(4-chlorophenyl)(thien-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-benzhydryl-3-[(ethylsulfonyl)(phenyl)methylene]-azetidine,1-[bis(4-chlorophenyl)methyl]-3-{{3-[N-(4-methylpiperazinyl)carbamoyl]phenyl}(methylsulfonyl)methylene}azetidine,1-[bis(4-chlorophenyl)methyl]-3-{[3-(2,2-dimethylcarbohydrazido)phenyl](methylsulfonyl)methylene)azetidine,1-[bis(thien-2-yl)methyl]-3-[3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(p-tolyl)methyl]-3-[(methylsulfonyl)(phenyl)methylene]azetidine,1-[(4-chlorophenyl)(4-hydroxymethylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]-azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine,(RS)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(R)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,(S)-1-[(4-chlorophenyl)(thiazol-2-yl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine,and(RS)-1-[bis(4-chlorophenyl)methyl]-3-hydroxy-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methyl]azetidine,their optical isomers and their salts with an inorganic or organic acid.16. The method of claim 1, wherein said compound is selected from:1-[bis(4-chlorophenyl)methyl]-3-[(2-isobutyl-aminocarbonylthien-5-yl)(methylsulfonyl)methylene]azetidine,1-[bis(4-chlorophenyl)methyl]-3-[(3-methoxycarbonylphenyl)(methylsulfonyl)methyl-(RS)azetidin-3-ol,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-4-yl)methyl-(RS)azetidin-3-ol,1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(pyridin-3-yl)methyl-(RS)azetidin-3-ol,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-morpholin-4-yl-propyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-dimethylaminopropyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-pyrrolidin-1-ylethyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylamino-1-methylethyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-piperidin-1-ylbenzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-isobutylbenzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(3-imidazol-1-ylpropyl)benzamide,3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-dimethylaminoethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoicacid N′-methylhydrazide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-morpholin-4-ylethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(1-ethylpyrrolidin-2-ylmethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-dimethylpropyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclohexylmethylbenzamide,and3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-cyclopropylmethylbenzamide,their optical isomers and their salts with an inorganic or organic acid.17. The method of claim 1, wherein said compound is selected from:3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-methylbutyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-phenylpropyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(tetrahydrofuran-2-ylmethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2,2-diphenylethyl)benzamide,3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}-methanesulfonylmethyl)-N-(2-ethylbutyl)benzamide,4-{[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)benzoylamino]methyl}cyclohexanecarboxylic acid methyl ester,2-amino-1-{4-[3-({1-[bis-(4-chlorophenyl)methyl]-azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}ethanone,(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)carbamicacid tert-butyl ester,1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-methylaminoethanone,(2-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-oxoethyl)-N-methylcarbamicacid tert-butyl ester,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carbothioicacid N-methylamide,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid N-methylamide,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid methyl ester,1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine,1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-ethylpiperazine,4-acetyl1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,1-{4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazin-1-yl}-2-dimethylaminoethanone,1-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine,4-[3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine-1-carboxylicacid tert-butyl ester,1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methylene]azetidine,3-acetoxy-1-[bis(4-methoxycarbonylphenyl)methyl]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl-(RS)azetidine,(RS)-4-[4-((4-chlorophenyl){3-[(3,5-difluorophenyl)methanesulfonylmethylene]azetidin-1-yl}methyl)benzyl]morpholine,and4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}butyl)morpholine,4-(4-{3-[(1-benzhydrylazetidin-3-ylidene)methanesulfonylmethyl]phenoxy}propyl)morpholine,their optical isomers and their salts with an inorganic or organic acid.18. The method of claim 1, wherein aid condition is selected fromschizophrenia, anxiety disorders, depression, epilepsy,neurodegeneration, cerebellar and spinocerebellar disorders, cognitivedisorders, cranial trauma, panic attacks, peripheral neuropathies,glaucomas, migraine, Parkinson's disease, Alzeimer's disease,Huntington's chorea, Raynaud's syndrome, tremor, obsessive-compulsivedisorder, senile dementia, and obesity.
 19. The method of claim 1,wherein said drug of abuse is selected from opioids, barbiturates,cannabis, cocaine, amphetamine, phencyclide, hallucinogens, andbenzodiazepines.